Download Programmed necrosis, not apoptosis, is a key mediator of cell loss

EW
Cell Death Differ. 2013 Aug 16. doi: 10.1038/cdd.2013.109. [Epub ahead of print]
Programmed necrosis, not apoptosis, is a key mediator of cell
loss and DAMP-mediated inflammation in dsRNA-induced
retinal degeneration.
Murakami Y, Matsumoto H, Roh M, Giani A, Kataoka K, Morizane Y, Kayama M, Thanos
A, Nakatake S, Notomi S, Hisatomi T, Ikeda Y, Ishibashi T, Connor KM, Miller JW, Vavvas
DG.
Source
1] Department of Ophthalmology, Retina Service, Angiogenesis Laboratory, Massachusetts Eye and
Ear Infirmary, Harvard Medical School, Boston, MA, USA [2] Department of Ophthalmology, Graduate
School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Abstract
There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death
and inflammation are important biological processes thought to have central role in AMD. Here we show
that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse
model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to
photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I : C) caused necrosis of
the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/- mice,
both necrosis and inflammation were prevented, providing substantial protection against poly(I : C)-induced
retinal degeneration. Moreover, after poly(I : C) injection, Rip3-/- mice displayed decreased levels of proinflammatory cytokines (such as TNF-α and IL-6) in the retina, and attenuated intravitreal release of highmobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I : C)induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and
dampened TNF-α and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency
did not modulate directly TNF-α and IL-6 production after poly(I : C) stimulation in RPE cells or
macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may
promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic
targets for diseases such as AMD.
Nature. 2013 Aug 18. doi: 10.1038/nature12436. [Epub ahead of print]
Pathogen blocks host death receptor signalling by arginine
GlcNAcylation of death domains.
Li S, Zhang L, Yao Q, Li L, Dong N, Rong J, Gao W, Ding X, Sun L, Chen X, Chen S, Shao
F.
Source
1] College of Biological Sciences, China Agricultural University, Beijing 100094, China [2] National
Institute of Biological Sciences, Beijing 102206, China [3].
Abstract
The tumour necrosis factor (TNF) family is crucial for immune homeostasis, cell death and inflammation.
These cytokines are recognized by members of the TNF receptor (TNFR) family of death receptors,
including TNFR1 and TNFR2, and FAS and TNF-related apoptosis-inducing ligand (TRAIL) receptors.
Death receptor signalling requires death-domain-mediated homotypic/heterotypic interactions between the
receptor and its downstream adaptors, including TNFR1-associated death domain protein (TRADD) and
FAS-associated death domain protein (FADD). Here we discover that death domains in several proteins,
including TRADD, FADD, RIPK1 and TNFR1, were directly inactivated by NleB, an enteropathogenic
Escherichia coli (EPEC) type III secretion system effector known to inhibit host nuclear factor-κB (NF-κB)
signalling. NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that
specifically modified a conserved arginine in these death domains (Arg 235 in the TRADD death domain).
NleB GlcNAcylation (the addition of GlcNAc onto a protein side chain) of death domains blocked
homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFR1 complex, thereby
disrupting TNF signalling in EPEC-infected cells, including NF-κB signalling, apoptosis and necroptosis.
Type-III-delivered NleB also blocked FAS ligand and TRAIL-induced cell death by preventing formation of
a FADD-mediated death-inducing signalling complex (DISC). The arginine GlcNAc transferase activity of
NleB was required for bacterial colonization in the mouse model of EPEC infection. The mechanism of
action of NleB represents a new model by which bacteria counteract host defences, and also a previously
unappreciated post-translational modification.
J Clin Oncol. 2013 Aug 5. [Epub ahead of print]
Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib
(GSK2118436) in Patients With Metastatic Melanoma.
Ascierto PA, Minor D, Ribas A, Lebbe C, O'Hagan A, Arya N, Guckert M, Schadendorf
D, Kefford RF, Grob JJ, Hamid O, Amaravadi R, Simeone E, Wilhelm T,Kim KB, Long
GV, Martin AM, Mazumdar J, Goodman VL, Trefzer U.
Source
Paolo A. Ascierto, Ester Simeone, Instituto Nazionale Tumori Fondazione "G. Pascale," Napoli, Italy;
David Minor, California Pacific Center for Melanoma Research and Treatment, San Francisco; Antoni
Ribas, Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Omid Hamid,
Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles,
CA; Anne O'Hagan, Niki Arya, Mary Guckert, Anne-Marie Martin, Jolly Mazumdar, Vicki L. Goodman,
GlaxoSmithKline Oncology, Collegeville; Ravi Amaravadi, Abramson Cancer Center, University of
Pennsylvania, Philadelphia, PA; Kevin B. Kim, The University of Texas MD Anderson Cancer Center,
Houston, TX; Celeste Lebbe, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Paris,
Université Paris Diderot, Paris; Jean-Jacques Grob, Aix-Marseille University, Assistance PubliqueHôpitaux de Marseille, Hôpital Timone, Marseille, France; Dirk Schadendorf, University Hospital
Essen, Essen; Tabea Wilhelm, Uwe Trefzer, Charité-Universitätsmedizin, Berlin, Germany; Richard F.
Kefford, Georgina V. Long, Westmead Hospital and Melanoma Institute Australia, University of
Sydney, Sydney, Australia.
Abstract
PURPOSE:
Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm,
phase II study assessed the safety and clinical activity of dabrafenib in BRAFV600E/K mutation-positive
metastatic melanoma (mut+ MM).
PATIENTS AND METHODS:
Histologically confirmed patients with stage IV BRAFV600E/K mut+ MM received oral dabrafenib 150 mg twice
daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was
investigator-assessed overall response rate in BRAFV600E mut+ MM patients. Secondary end points included
progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison
of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and
the evaluation of cfDNA as a predictor of clinical outcome.
RESULTS:
Seventy-six patients with BRAFV600E and 16 patients with BRAFV600K mut+ MM were enrolled onto the study.
In the BRAFV600E group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five
patients (7%) with complete responses. Two patients (13%) with BRAFV600K mut+ MM had a confirmed
partial response (95% CI, 0 to 28.7). In the BRAFV600E and BRAFV600K groups, median PFS was 6.3 months
and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs
were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a
serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted
response rate and PFS in BRAFV600E mut+ MM patients.
CONCLUSION:
Dabrafenib was well tolerated and clinically active in patients with BRAFV600E/K mut+ MM. cfDNA may be a
useful prognostic and response marker in future studies.
Nature. 2013 Aug 11. doi: 10.1038/nature12441. [Epub ahead of print]
Mechanism of MEK inhibition determines efficacy in mutant
KRAS- versus BRAF-driven cancers.
Hatzivassiliou G, Haling JR, Chen H, Song K, Price S, Heald R, Hewitt JF, Zak M, Peck
A, Orr C, Merchant M, Hoeflich KP, Chan J, Luoh SM, Anderson DJ,Ludlam MJ, Wiesmann
C, Ultsch M, Friedman LS, Malek S, Belvin M.
Source
Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California
94080, USA.
Abstract
KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK
pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK
inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive
single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less
robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK
activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for
optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK
inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in
phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking
MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated
MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior
efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III
clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours
versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these
distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine
whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to
improved clinical responses in patients.
J Invest Dermatol. 2013 Aug 16. doi: 10.1038/jid.2013.347. [Epub ahead of print]
RAF inhibition overcomes resistance to TRAIL-induced
apoptosis in melanoma cells.
Berger A, Quast SA, Plötz M, Kuhn NF, Trefzer U, Eberle J.
Source
Department of Dermatology and Allergy, Skin Cancer Center, University Medical Center Charité,
Berlin, Germany.
Abstract
Mutated BRAF represents a critical oncogene in melanoma, and selective inhibitors have been approved
for melanoma therapy. However, the molecular consequences of RAF inhibition in melanoma cells
remained largely elusive. Here, we investigated the effects of the pan-RAF inhibitor L-779,450, which
inhibited cell proliferation both in BRAF-mutated and WT melanoma cell lines. It furthermore enhanced
apoptosis in combination with the death ligand TRAIL (TNF-related apoptosis-inducing ligand) and
overcame TRAIL resistance in melanoma cells. Enhanced apoptosis coincided with activation of
mitochondrial pathways, seen by loss of mitochondrial membrane potential and release of cytochrome c,
SMAC and AIF. Subsequently, caspases-9 and -3 were activated. Apoptosis induction by L-779,450/TRAIL
was prevented by Bcl-2 overexpression and was dependent on Bax. Thus, activation of Bax by L-779,450
alone was demonstrated by Bax conformational changes, whereas Bak was not activated. Furthermore, the
BH3-only protein Bim was upregulated in response to L-779,450. The significant roles of Smac, Bax and
Bim in this setting were proven by si-RNA-mediated knockdown experiments. L-779,450 also resulted in
morphological changes indicating autophagy confirmed by the autophagy marker LC3-II. The proapoptotic
effects of L-779,450 may explain the antitumor effects of RAF inhibition and may be considered when
evaluating RAF inhibitors for melanoma therapy.Journal of Investigative Dermatology accepted article
preview online, 16 August 2013. doi:10.1038/jid.2013.347.
Sci Rep. 2013 Aug 2;3:2344. doi: 10.1038/srep02344.
Lys63-linked polyubiquitination of BRAF at lysine 578 is
required for BRAF-mediated signaling.
An L, Jia W, Yu Y, Zou N, Liang L, Zhao Y, Fan Y, Cheng J, Shi Z, Xu G, Li G, Yang
J, Zhang H.
Source
1] Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030,
USA [2].
Abstract
The RAF kinase family is essential in mediating signal transduction from RAS to ERK. BRAF constitutively
active mutations correlate with human cancer development. However, the precise molecular regulation
of BRAF activation is not fully understood. Here we report that BRAF is modified by Lys63-linked
polyubiquitination at lysine 578 within its kinase domain once it is activated by gain of constitutively active
mutation or epidermal growth factor (EGF) stimulation. Substitution of BRAF lysine 578 with arginine
(K578R) inhibited BRAF-mediated ERK activation. Furthermore, ectopic expression of BRAF K578R
mutant inhibited anchorage-independent colony formation of MCF7 breast cancer cell line. Our studies
have identified a previously unrecognized regulatory role of Lys63-linked polyubiquitination in BRAFmediated normal and oncogenic signalings.
Cancer Res. 2013 Aug 15. [Epub ahead of print]
BRD4 sustains proliferation and represents a new target for
epigenetic therapy in melanoma.
Segura MF, Fontanals-Cirera B, Gaziel-Sovran A, Guijarro MV, Hanniford D, Zhang
G, Gonzalez-Gomez P, Morante M, Jubierre L, Zhang W, Darvishian F,Ohlmeyer M, Osman
I, Zhou MM, Hernando E.
Source
Pediatric Oncology, Vall d'Hebron Research Institute.
Abstract
Metastatic melanoma remains a mostly incurable disease. Although newly approved targeted therapies are
efficacious in a subset of patients, resistance and relapse rapidly ensue. Alternative therapeutic strategies
to manipulate epigenetic regulators and disrupt the transcriptional program that maintains tumor cell
identity are emerging. Bromodomain and extraterminal domain (BET) proteins are epigenome readers
known to exert key roles at the interface between chromatin remodeling and transcriptional regulation. Here
we report that BRD4, a BET family member, is significantly upregulated in primary and metastatic
melanoma tissues compared to melanocytes and nevi. Treatment with BET inhibitors impaired melanoma
cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly
recapitulated by individual silencing of BRD4. RNA sequencing of BET inhibitor-treated cells followed by
gene ontology analysis showed a striking impact on transcriptional programs controlling cell growth,
proliferation, cell-cycle regulation and differentiation. In particular, we found that, rapidly after BET
displacement, key cell cycle genes (SKP2, ERK1 and c-MYC) were downregulated concomitantly with the
accumulation of CDK inhibitors (p21, p27), followed by melanoma cell cycle arrest. Importantly, BET
inhibitor efficacy was not influenced by BRAF or NRAS mutational status, opening the possibility of using
these small molecule compounds to treat patients for whom no effective targeted therapy exists.
Collectively, our study reveals a critical role for BRD4 in melanoma tumor maintenance, and renders it a
legitimate and novel target for epigenetic therapy directed against the core transcriptional program of
melanoma.
ARAM
[p53]
Proc Natl Acad Sci U S A. 2013 Aug 14. [Epub ahead of print]
Stapled α-helical peptide drug development: A potent dual inhibitor
of MDM2 and MDMX for p53-dependent cancer therapy.
Chang YS, Graves B, Guerlavais V, Tovar C, Packman K, To KH, Olson KA, Kesavan K, Gangurde P,
Mukherjee A, Baker T, Darlak K, Elkin C, Filipovic Z, Qureshi FZ, Cai H, Berry P, Feyfant E, Shi XE,
Horstick J, Annis DA, Manning AM, Fotouhi N, Nash H, Vassilev LT, Sawyer TK.
Source
Aileron Therapeutics, Inc., Cambridge, MA 02139.
Abstract
Stapled α-helical peptides have emerged as a promising new modality for a wide range of therapeutic
targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which
effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds
both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer
cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action.
A high resolution (1.7-Å) X-ray crystal structure reveals its molecular interactions with the target
protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon
staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent
tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high
correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and
tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept
that stapled peptides can be developed as therapeutically relevant inhibitors of protein-protein
interaction and may offer a viable modality for cancer therapy.
Cancer Res. 2013 Aug 13. [Epub ahead of print]
Notch1 is required for Kras-induced lung adenocarcinoma and
controls tumor cell survival via p53.
Licciulli S, Avila JL, Hanlon L, Troutman S, Cesaroni M, Kota S, Keith B, Simon MC, Pure E, Radtke F,
Capobianco AJ, Kissil JL.
Source
Cancer Biology, The Scripps Research Institute - Florida.
Abstract
Over the last few years, the Notch pathway has been implicated in a number of malignancies with
different roles that are cell and tissue-type dependent. Notch1 is a putative oncogene in NSCLC and
activation of the pathway represents a negative prognostic factor. To establish the role of Notch1 in
lung adenocarcinoma we directly assessed its requirement in K-ras-induced tumorigenesis in vivo,
employing an autochthonous model of lung adenocarcinoma with concomitant expression of
oncogenic K-ras and deletion of Notch1. We find that Notch1 function is required for lung tumor
initiation via suppression of p53-mediated apoptosis in vivo, through the regulation of p53 stability.
These findings implicate Notch1 as a critical effector in K-ras-driven lung adenocarcinoma and as a
regulator of p53 at a post-translational level. Moreover, our study provides new insights to explain, at
a molecular level, the correlation between Notch1 activity and poor prognosis in NSCLC patients
carrying wild type p53. This information is critical for the design and implementation of new
therapeutic strategies in this cohort of patients representing 50% of all NSCLC cases.
[OTUB1]
Nat Struct Mol Biol. 2013 Aug 18. doi: 10.1038/nsmb.2655. [Epub ahead of print]
E2 ubiquitin-conjugating enzymes regulate the deubiquitinating
activity of OTUB1.
Wiener R, Dibello AT, Lombardi PM, Guzzo CM, Zhang X, Matunis MJ, Wolberger C.
Source
1] Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine,
Baltimore, Maryland, USA. [2] Howard Hughes Medical Institute, Baltimore, Maryland, USA. [3] [4].
Abstract
OTUB1 is a Lys48-specific deubiquitinating enzyme that forms a complex in vivo with E2 ubiquitin
(Ub)-conjugating enzymes including UBC13 and UBCH5. OTUB1 binds E2~Ub thioester
intermediates and prevents ubiquitin transfer, thereby noncatalytically inhibiting accumulation of
polyubiquitin. We report here that a second role of OTUB1-E2 interactions is to stimulate OTUB1
cleavage of Lys48 polyubiquitin. This stimulation is regulated by the ratio of charged to uncharged E2
and by the concentration of Lys48-linked polyubiquitin and free ubiquitin. Structural and biochemical
studies of human and worm OTUB1 and UBCH5B show that the E2 enzyme stimulates binding of the
Lys48 polyubiquitin substrate by stabilizing folding of the OTUB1 N-terminal ubiquitin-binding helix.
Our results suggest that OTUB1-E2 complexes in the cell are poised to regulate polyubiquitin chain
elongation or degradation in response to changing levels of E2 charging and available free ubiquitin.
MS
PTEN
Science. 2013 Jul 26;341(6144):395-9. doi: 10.1126/science.1236188.
Nuclear PTEN controls DNA repair and sensitivity to genotoxic
stress.
Bassi C, Ho J, Srikumar T, Dowling RJ, Gorrini C, Miller SJ, Mak TW, Neel BG, Raught B, Stambolic
V.
Source
Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
Abstract
Loss of function of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor
suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the
phosphatidylinositol 3-kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where
its function remains poorly understood. We demonstrate that SUMOylation (SUMO, small ubiquitinlike modifier) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMOPTEN was rapidly excluded from the nucleus dependent on the protein kinase ataxia telangiectasia
mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, whereas PTENdeficient cells were susceptible to killing by a combination of genotoxic stress and a small-molecule
PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy
for patients with PTEN-deficient tumors.
Science. 2013 Jul 26;341(6144):355-6. doi: 10.1126/science.1242541.
Cell biology. Where is PTEN?
Leslie NR, Brunton VG.
Source
Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical
Sciences, Heriot Watt University, Edinburgh EH14 4AS, UK. [email protected]
AMPK
Clin Cancer Res. 2013 Aug 13. [Epub ahead of print]
Prognostic significance of AMPK activation and therapeutic effects
of metformin in hepatocellular carcinoma.
Wang H, Zheng LY, Yang W, Wu FQ, Wang C, Yu L, Tang L, Qiu B, Li YQ, Guo L, Wu MC, Feng GS,
Zou D.
Source
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute,
The Second Military Medical University.
Abstract
PURPOSE:
The AMP-activated protein kinase (AMPK) serves as an energy sensor in eukaryotic cells and
occupies a central role in linking metabolism and cancer development. However, the phosphorylation
status of AMPK and its therapeutic value in human hepatocellular carcinoma (HCC) remain unclear.
EXPERIMENTAL DESIGN:
The phosphorylation status of AMPK (Thr172) was determined by immunoblotting and
immunostaining in specimens from 273 HCC patients (including 253 HBV-related HCC patients).
Kaplan-Meier survival analysis was used to determine the correlation with prognosis. The effects of
therapeutic metformin/AMPK activation were assessed in cultured human HCC cell lines and primary
HCC cells in vitro and in xenograft tumors model in vivo. To define mechanisms of anticancer effects
of metformin, we examined its influence on AMPK activation and nuclear factor-κB (NF-κB) pathway.
RESULTS:
AMPK is dysfunctional in HCC patients, and low p-AMPK staining is correlated with aggressive
clinicopathologic features and poor prognosis. Activation of AMPK by metformin not only inhibited
HCC cells growth in vitro and in vivo, also augmented cisplatin-induced growth inhibition in HCC cells.
Knockdown of AMPKα expression can greatly decrease the inhibitory effect of metformin, indicating
AMPK activation is required for the anticancer action of metformin. Mechanistically, metformin/AMPK
activation inhibited NF-κB signaling through upregulation of IκBα. Activation of NF-κB signaling by
ectopic expression of P65 or overexpression of an undegradable mutant form of IκBα attenuated the
anticancer effects of metformin.
CONCLUSIONS:
These results present novel insight into a critical role of AMPK in HCC progression. Anticancer effects
of therapeutic metformin/AMPK activation unravel metformin's potential in treatment of HCC.
Cell Metab. 2013 Aug 6;18(2):251-64. doi: 10.1016/j.cmet.2013.06.017.
AMPKα1 Regulates Macrophage Skewing at the Time of Resolution
of Inflammation during Skeletal Muscle Regeneration.
Mounier R, Théret M, Arnold L, Cuvellier S, Bultot L, Göransson O, Sanz N, Ferry A, Sakamoto K,
Foretz M, Viollet B, Chazaud B.
Source
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR8104, Paris 75014, France;
Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
Abstract
Macrophages control the resolution of inflammation through the transition from a proinflammatory (M1)
to an anti-inflammatory (M2) phenotype. Here, we present evidence for a role of AMPKα1, a master
regulator of energy homeostasis, in macrophage skewing that occurs during skeletal muscle
regeneration. Muscle regeneration was impaired in AMPKα1(-/-) mice. In vivo loss-of-function (LysMCre;AMPKα1(fl/fl) mouse) and rescue (bone marrow transplantation) experiments showed that
macrophagic AMPKα1 was required for muscle regeneration. Cell-based experiments revealed that
AMPKα1(-/-) macrophages did not fully acquire the phenotype or the functions of M2 cells. In vivo,
AMPKα1(-/-) leukocytes did not acquire the expression of M2 markers during muscle regeneration.
Skewing from M1 toward M2 phenotype upon phagocytosis of necrotic and apoptotic cells was
impaired in AMPKα1(-/-) macrophages and when AMPK activation was prevented by the inhibition of
its upstream activator, CaMKKβ. In conclusion, AMPKα1 is crucial for phagocytosis-induced
macrophage skewing from a pro- to anti-inflammatory phenotype at the time of resolution of
inflammation.
J Clin Invest. 2013 Jul 1;123(7):2907-20. doi: 10.1172/JCI67841. Epub 2013 Jun 10.
Metabolic stress regulates cytoskeletal dynamics and metastasis of
cancer cells.
Caino MC, Chae YC, Vaira V, Ferrero S, Nosotti M, Martin NM, Weeraratna A, O'Connell M, Jernigan
D, Fatatis A, Languino LR, Bosari S, Altieri DC.
Abstract
Metabolic reprogramming is an important driver of tumor progression; however, the metabolic
regulators of tumor cell motility and metastasis are not understood. Here, we show that tumors
maintain energy production under nutrient deprivation through the function of HSP90 chaperones
compartmentalized in mitochondria. Using cancer cell lines, we found that mitochondrial HSP90
proteins, including tumor necrosis factor receptor-associated protein-1 (TRAP-1), dampen the
activation of the nutrient-sensing AMPK and its substrate UNC-51-like kinase (ULK1), preserve
cytoskeletal dynamics, and release the cell motility effector focal adhesion kinase (FAK) from
inhibition by the autophagy initiator FIP200. In turn, this results in enhanced tumor cell invasion in low
nutrients and metastatic dissemination to bone or liver in disease models in mice. Moreover, we found
that phosphorylated ULK1 levels were correlated with shortened overall survival in patients with nonsmall cell lung cancer. These results demonstrate that mitochondrial HSP90 chaperones, including
TRAP-1, overcome metabolic stress and promote tumor cell metastasis by limiting the activation of
the nutrient sensor AMPK and preventing autophagy.
Cell Signal. 2013 Jul 27. pii: S0898-6568(13)00215-5. doi: 10.1016/j.cellsig.2013.07.017. [Epub
ahead of print]
MicroRNA-451 regulates AMPK/mTORC1 signaling and fascin1
expression in HT-29 colorectal cancer cells.
Chen MB, Wei MX, Han JY, Wu XY, Li C, Wang J, Shen W, Lu PH.
Source
Department of Medical Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, 91
Qianjin Road, Kunshan 215300, Jiangsu Province, China.
Abstract
The earlier studies have shown that Fascin1 (FSCN1), the actin bundling protein, is over-expressed in
colorectal cancers, and is associated with cancer cell progression. Here, we aimed to understand the
molecular mechanisms regulating FSCN1 expression by focusing on mammalian target of rapamycin
(mTOR) signaling and its regulator microRNA-451. We found that microRNA-451 was over-expressed
in multiple colorectal cancer tissues, and its expression was correlated with mTOR complex 1
(mTORC1) activity and FSCN1 expression. In cultured colorectal cancer HT-29 cells, knockdown of
FSCN1 by RNAi inhibited cell migration and proliferation. Activation of mTORC1 was required for
FSCN1 expression, HT-29 cell migration and proliferation, as RAD001 and rapamycin, two mTORC1
inhibitors, suppressed FSCN1 expression, HT-29 cell migration and proliferation. Meanwhile, forced
activation of AMP-activated protein kinase (AMPK), the negative regulator of mTORC1, by its
activators or by the genetic mutation, inhibited mTORC1 activation, FSCN1 expression, cell migration
and proliferation. In HT-29 cells, we found that over-expression of microRNA-451 inhibited AMPK
activation, causing mTORC1 over-activation and FSCN1 up-regulation, cells were with high migration
ability and proliferation rate. Significantly, these effects by microRNA-451 were largely inhibited by
mTORC1 inhibitors or the AMPK activator AICAR. On the other hand, knockdown of miRNA-451 by
the treatment of HT-29 cells with miRNA-451 antagomir inhibited mTORC1 activation and FSCN1
expression. The proliferation and migration of HT-29 cells after miRNA-45 knockdown were also
inhibited. Our results suggested that the over-expressed microRNA-451 in colon cancer cells might
inhibit AMPK to activate mTORC1, which mediates FSCN1 expression and cancer cell progression.
SSY
<oncogene>
Opportunities and hurdles in the treatment of BRCA1related breast cancer
R Drost1 and J Jonkers1
1Division
of Molecular Pathology and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute,
Amsterdam, The Netherlands
Correspondence: Dr J Jonkers, Division of Molecular Pathology and Cancer Genomics Centre Netherlands, The
Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, Noord-Holland 1066CX, The Netherlands. E-mail:
[email protected]
Received 16 April 2013; Revised 13 June 2013; Accepted 21 June 2013
Advance online publication 19 August 2013
Top of page
Abstract
BRCA1 functions as a classical tumor suppressor in breast and ovarian cancer.
While the role of BRCA1 in homology-directed repair of DNA double-strand
breaks contributes to its tumor suppressive activity, it also renders BRCA1deficient cells highly sensitive to DNA-damaging agents. Although BRCA1
deficiency is therefore considered to be an attractive therapeutic target, reactivation of BRCA1 by secondary mutations has been shown to cause therapy
resistance. In this review, we will assess the role of BRCA1 in both hereditary
and sporadic breast cancer and discuss how different functionalities of the
BRCA1 protein can contribute to its tumor suppressor function. In addition, we
will discuss how this knowledge on BRCA1 function can help to overcome the
hurdles encountered in the clinic and improve current treatment strategies for
patients with BRCA1-related breast cancer.
Keywords: BRCA1; breast cancer; treatment
Reviews
Opportunities and hurdles in the treatment of BRCA1-related breast cancer
R Drost and J Jonkers
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.329
Abstract | Full Text | PDF
The role of miR-150 in normal and malignant hematopoiesis
Y He, X Jiang and J Chen
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.346
Abstract | Full Text | PDF
Original Articles
Stefin B deficiency reduces tumor growth via sensitization of tumor cells to
oxidative stress in a breast cancer model
M Butinar, M T Prebanda, J Rajković, B Jerič, V Stoka, C Peters, T Reinheckel, A Krüger,
V Turk, B Turk and O Vasiljeva
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.314
Abstract | Full Text | PDF | Supplementary information
A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase
Substrate (MARCKS) reduces lung cancer metastasis
C-H Chen, P Thai, K Yoneda, K B Adler, P-C Yang and R Wu
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.336
Abstract | Full Text | PDF | Supplementary information
Inducible expression of hyperactive Syk in B cells activates Blimp-1-dependent
terminal differentiation
E Hug, E Hobeika, M Reth and H Jumaa
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.326
Abstract | Full Text | PDF | Supplementary information
MiR-155-mediated loss of C/EBPβ shifts the TGF-β response from growth
inhibition to epithelial-mesenchymal transition, invasion and metastasis in
breast cancer Open
J Johansson, T Berg, E Kurzejamska, M-F Pang, V Tabor, M Jansson, P Roswall, K Pietras,
M Sund, P Religa and J Fuxe
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.322
Abstract | Full Text | PDF | Supplementary information
Inflammatory lipid sphingosine-1-phosphate upregulates C-reactive protein via
C/EBPβ and potentiates breast cancer progression
E-S Kim, Y Cha, M Ham, J Jung, S G Kim, S Hwang, R Kleemann and A Moon
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.319
Abstract | Full Text | PDF
The telomere profile distinguishes two classes of genetically distinct cutaneous
squamous cell carcinomas
C Leufke, J Leykauf, D Krunic, A Jauch, H Holtgreve-Grez, B Böhm-Steuer, E-B Bröcker,
C Mauch, J Utikal, W Hartschuh, K J Purdie and P Boukamp
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.323
Abstract | Full Text | PDF | Supplementary information
p53 deficiency enhances mitotic arrest and slippage induced by
pharmacological inhibition of Aurora kinases
M Marxer, H T Ma, W Y Man and R Y C Poon
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.325
Abstract | Full Text | PDF | Supplementary information
Short Communications
The error-prone DNA polymerase ι provides quantitative resistance to lung
tumorigenesis and mutagenesis in mice
M Iguchi, M Osanai, Y Hayashi, F Koentgen and G-H Lee
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.331
Abstract | Full Text | PDF | Supplementary information
Bmi1 is required for tumorigenesis in a mouse model of intestinal cancer
M A Maynard, R Ferretti, K I Hilgendorf, C Perret, P Whyte and J A Lees
Oncogene advance online publication, August 19, 2013; doi:10.1038/onc.2013.333
Abstract | Full Text | PDF | Supplementary information
MH
The
Epigenetic
Modifier
Ubiquitin-specific
Protease 22 (USP22) Regulates Embryonic Stem
Cell Differentiation via Transcriptional Repression
of Sex-determining Region Y-box 2 (SOX2)
1. From the ‡Department of Cancer Biology, Jefferson Medical College, Thomas Jefferson
University, Philadelphia, Pennsylvania 19107 and
2. the §Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia,
Pennsylvania 19104
Abstract
Pluripotent embryonic stem cells (ESCs) undergo self-renewal until stimulated to
differentiate along specific lineage pathways. Many of the transcriptional networks that
drive reprogramming of a self-renewing ESC to a differentiating cell have been identified.
However, fundamental questions remain unanswered about the epigenetic programs that
control these changes in gene expression. Here we report that the histone ubiquitin
hydrolase ubiquitin-specific protease 22 (USP22) is a critical epigenetic modifier that
controls this transition from self-renewal to differentiation. USP22 is induced as ESCs
differentiate and is necessary for differentiation into all three germ layers. We further
report that USP22 is a transcriptional repressor of the locus encoding the core
pluripotency factor sex-determining region Y-box 2 (SOX2) in ESCs, and this repression
is required for efficient differentiation. USP22 occupies the Sox2 promoter and
hydrolyzes monoubiquitin from ubiquitylated histone H2B and blocks transcription of the
Sox2 locus. Our study reveals an epigenetic mechanism that represses the core
pluripotency transcriptional network in ESCs, allowing ESCs to transition from a state of
self-renewal into lineage-specific differentiation programs.
Inhibition of Protein Synthesis Alters Protein
Degradation through Activation of Protein Kinase
B (AKT)
1. From the ‡Department of Neurochemistry, New York State Institute for Basic Research in
Developmental Disabilities, Staten Island, New York 10314 and
2. the §Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu
226001, China
Abstract
The homeostasis of protein metabolism is maintained and regulated by the rates of
protein
biosynthesis and
degradation in
living systems. Alterations of protein
degradation may regulate protein biosynthesis through a feedback mechanism. Whether
a change in protein biosynthesis modulates protein degradation has not been reported.
In
this
study,
we
found
that
inhibition
of
protein
biosynthesis
induced
phosphorylation/activation of AKT and led to phosphorylation of AKT target substrates,
including FoxO1, GSK3α/β, p70S6K, AS160, and the E3 ubiquitin ligase MDM2.
Phosphorylation of ribosomal protein S6 was also modulated by inhibition of protein
biosynthesis. The AKT phosphorylation/activation was mediated mainly through the PI3K
pathway because it was blocked by the PI3K inhibitor LY294002. The activated AKT
phosphorylated MDM2 at Ser166 and promoted degradation of the tumor suppressor p53.
These findings suggest that inhibition of protein biosynthesis can alter degradation of
some proteins through activation of AKT. This study reveals a novel regulation of protein
degradation and calls for caution in blocking protein biosynthesis to study the half-life of
proteins.