Download β-catenin confers resistance to PI3K and AKT inhibitors and subverts

β-catenin confers resistance to PI3K and AKT
inhibitors and subverts FOXO3a to promote
metastasis in colon cancer
Nature Medicine 18, 892–901 (2012)
Speaker: 郭佩芳
Commentator: 洪澤民 老師
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Colon cancer is a leading cause of death
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CA CANCER J CLIN 2011;61:69–90
Regulation of FOXO transcription factors by the
PI3K-AKT pathway.
Oellerich M F , Potente M Circulation Research . 2012;110:1238-1251
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PI3K - AKT signaling inhibitor inhibit cell growth
and induce apoptosis
• Recent developments in anti-cancer agents targeting PI3K, Akt and
mTORC1/2.
Recent Pat. Anticancer Drug Discov. 6, 210–236 (2011)
• Akt/protein kinase B signaling inhibitor-2, a selective small molecule
inhibitor of Akt signaling with antitumor activity in cancer cells
overexpressing Akt
Cancer Res. 64, 4394–4399 (2004)
• Novel phosphatidylinositol 3-kinase inhibitor NVP-BKM120 induces
apoptosis in myeloma cells and shows synergistic anti-myeloma activity
with dexamethasone
J Mol Med (Berl) (2011)
4
β-catenin bind Tcf/Lef to promote the
transcription of Wnt target genes
Tumorigenesis
, metastasis
Annu. Rev. Cell Dev. Biol. 2004. 20:781–810
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β-catenin enhance FOXO transcriptional
activity and interacted with FOXO3a
In DLD-1 cells
Science 308, 1181–1184 (2005)
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Motivation
Wnt/β-catenin modulates the function of PI3K/AKT inhibitors
through regulating FOXO3a activity in colon cancer .
PIK3
inhibitor
Wnt
AKT
β-catenin
Other effects
(such as metastasis)
FOXO3a
Cell death
Tumorigenesis
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Specific Aims
• Aim1:Nuclear FOXO3a and β-catenin concentrations
in colon cancer
• Ami2:β-catenin diverts FOXO3a-induced apoptosis to
metastasis
• Ami3:FOXO3a and β-catenin co-regulate metastasisrelevant genes
• Ami4:AKT inhibition induces metastasis cooperating
with β-catenin
• Ami5:β-catenin confers resistance to PI3K and AKT
inhibitors
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High nuclear concentrations of FOXO3a and β-catenin correlate
with metastatic stage in patients with colon cancer.
r: nuclear colocalization ratio
n : the number of cases
R : coefficient of correlation
r.u. : relative units
patient 1
patient 2
patient 3
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High nuclear concentrations of FOXO3a and β-catenin correlate
with shorter survival in patients with colon cancer.
High : 25.7 months median survival time, n=58
Low: 33.7 months median survival time ,n=55
High : 21.03 months median survival time, n=11
Low: 28.9 months median survival time ,n=102
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summary
• High nuclear concentrations of FOXO3a and βcatenin correlate with metastatic stage and
poor survival in patients with colon cancer.
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Specific Aims
• Aim1:Nuclear FOXO3a and β-catenin concentrations
in colon cancer
• Ami2:β-catenin diverts FOXO3a-induced apoptosis to
metastasis
• Ami3:FOXO3a and β-catenin co-regulate metastasisrelevant genes
• Ami4:AKT inhibition induces metastasis cooperating
with β-catenin
• Ami5:β-catenin confers resistance to PI3K and AKT
inhibitors
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Inducible nuclear expression of
FOXO3a and b-catenin
4-hydroxy-tamoxifen
mRNA
FOXO3A ER
FOXO3a
overexpression
In nuclear
pLHCX-HA-FOXO3a(A3):ERTM
β-catenin -S33Y
IRSE
mRNA
eGFP
doxycycline
β-catenin
overexpression
In nuclear
pSIN-TRE-Flag-β-cateninS33Y-IRES-GFP
IRSE : Internal ribosome entry site
eGFP : enhance GFP
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FOXO3a and β-catenin modulate colon cancer cell
proliferation and apoptosis.
DLD-1 human colon cells
4OHT : 4-hydroxy-tamoxifen
DOX : doxycycline
DLD-1Fβ-C7 cells
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FOXO3a and β-catenin modulate colon cancer cell
proliferation and apoptosis.
CDKN1A (p21CIP1): FOXO3a target gene
LEF1 : TCF target gene
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FOXO3a and β-catenin modulate colon cancer cell
proliferation and apoptosis.
subcutaneously with DLD-1Fβ cells in nude mice
Nuclear FOXO3a and β-catenin inhibit colon cancer cell proliferation and apoptosis.
eGFP+ : β-catenin enhanced GFP
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Nuclear FOXO3a and β-catenin drive
cell scattering.
Scatter : cell dispersion
4OHT+DOX
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Nuclear FOXO3a and β-catenin drive
cell metastasis.
HT29Fβ cells injected in the
cecum walls of the nude mice
Primary colon cancer
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summary
• Nuclear β-catenin inhibits FOXO3a-induced
apoptosis and promotes metastasis of colon
cancer cells.
Specific Aims
• Aim1:Nuclear FOXO3a and β-catenin concentrations
in colon cancer
• Ami2:β-catenin diverts FOXO3a-induced apoptosis to
metastasis
• Ami3:FOXO3a and β-catenin co-regulate metastasisrelevant genes
• Ami4:AKT inhibition induces metastasis cooperating
with β-catenin
• Ami5:β-catenin confers resistance to PI3K and AKT
inhibitors
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FOXO3a and β-catenin regulate a defined
gene expression program.
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FOXO3a and β-catenin regulate a defined
gene expression program.
Dev. Biol. 308, 485–493 (2007)
Gene Expr. Patterns 2, 17–22 (2002)
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FOXO3a and β-catenin regulate a defined
gene expression program.
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summary
• Nuclear FOXO3a and β-catenin induces
expression of metastasis-related genes.
Specific Aims
• Aim1:Nuclear FOXO3a and β-catenin concentrations
in colon cancer
• Ami2:β-catenin diverts FOXO3a-induced apoptosis to
metastasis
• Ami3:FOXO3a and β-catenin co-regulate metastasisrelevant genes
• Ami4:AKT inhibition induces metastasis cooperating
with β-catenin
• Ami5:β-catenin confers resistance to PI3K and AKT
inhibitors
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AKT inhibition by API-2 promotes metastasis of
cells with high nuclear β-catenin content.
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AKT inhibition by API-2 promotes metastasis of
cells with high nuclear β-catenin content.
DOX/API-2
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AKT inhibition by API-2 promotes metastasis of
cells with high nuclear β-catenin content.
BLI : bioluminescence
API-2+DOX
Primary colon cancer bioluminescence signal
DOX+API-2
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Summary
• Treatment of Akt inhibitor induces metastasis
when nuclear β-catenin expression is
increased.
Specific Aims
• Aim1:Nuclear FOXO3a and β-catenin concentrations
in colon cancer
• Ami2:β-catenin diverts FOXO3a-induced apoptosis to
metastasis
• Ami3:FOXO3a and β-catenin co-regulate metastasisrelevant genes
• Ami4:AKT inhibition induces metastasis cooperating
with β-catenin
• Ami5:β-catenin confers resistance to PI3K and AKT
inhibitors
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High nuclear β-catenin concentrations confer resistance to
PI3K and AKT inhibitors in colon cancer patient-derived cells.
subcutaneous injection in nonobese diabetic severe
combined immunodeficient (NOD-SCID) mice
XAV-939: Wnt/ β-catenin inhibitor
LY-2940002 : PI3K inhibitors
BKM120: PI3K inhibitors
API-2 : : AKT inhibitors
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High nuclear β-catenin concentrations confer resistance to
PI3K and AKT inhibitors in colon cancer patient-derived cells.
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High nuclear β-catenin concentrations confer resistance to
PI3K and AKT inhibitors in colon cancer patient-derived cells.
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Conclusion
Tankyrase inhibtor : XAV-939
Nature Medicine 18, 854–856 (2012)
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Discussion
• On the contrary, most studies have defined FOXO proteins as
tumor suppressors, as they induce cell-cycle arrest and
apoptosis.
Oncogene 27, 2276–2288 (2008)
Nat. Rev. Mol. Cell Biol. 8, 440–450 (2007)
• The combined knockdown of FOXO1, FOXO3 and FOXO4 in
mice is responsible for tumor initiation
Cell 128, 309–323 (2007)
• Foxo3a drives proliferation in anaplastic thyroid carcinoma via
transcriptional regulation of cyclin A1
Journal of cell science ,2012 Jun 20
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Thank you for your addition !!
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