Download Can defective TGFβ signaling be an Achilles heel in human cancer?

[Chinese Journal of Cancer 27:8, 180‑182; August 2008]; ©2008 Sun Yat‑Sen University Cancer Center
Mini‑Review
Can defective TGFβ signaling be an Achilles heel in human cancer?
David A. Foster* and Noga Gadir†
Department of Biological Sciences; Hunter College of the City University of New York; New York, New York, USA
†Current
Address: Department of Molecular Genetics; Weizmann Institute of Science; Rehovot, Israel
Abbreviations: CDK2, cyclin‑dependent kinase 2; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol‑3‑kinase; PLD,
phospholipase D; TGFβ, transforming growth factor‑β
Key words: TGFβ, mTOR, rapamycin, apoptosis, survival signals
Survival signals in cancer cells activate mTOR—­the ­mammalian
target of rapamycin. mTOR suppresses TGFβ signals that arrest cell
cycle progression in late G1—thus activated mTOR prevents cell
cycle arrest at a checkpoint mediated by TGFβ. Rapamycin treat‑
ment resurrects TGFβ signals causing G1 arrest. Defects in TGFβ
signaling are common in human cancer, and ironically, cancer cells
with defective TGFβ signaling that do not arrest in G1, instead
undergo apoptosis when treated with rapamycin. Thus, defective
TGFβ signaling may represent an Achilles heel for rational ­therapeutic
targeting of cancer cells using ­rapamycin‑based ­strategies.
A critical hurdle in tumorigenesis is the suppression of default
apoptotic programs that constitute what is likely the first line of
defense against cancer.1 Avoiding apoptosis involves the activation of
what has come to be known as “survival signals”. An emerging theme
for survival signals is the activation of mTOR—the mammalian
target of rapamycin.2 Survival signals generated by phosphatidylinos‑
itol‑3‑kinase (PI3K) and phospholipase D (PLD) both lead to the
activation of mTOR.3‑5 mTOR is a kinase that phosphorylates
substrates involved in the regulation of translation, which has
been implicated in tumorigenesis.6 mTOR has also been shown
to suppress transforming growth factor‑β (TGFβ) signaling.7‑10
Importantly, signals generated by both PI3K and PLD suppress
TGFβ signaling.9,11 The ability of PI3K and PLD to suppress TGFβ
signaling is likely an important component of mTOR‑dependent
survival signaling in that TGFβ leads to G1 cell cycle arrest.7
Consistent with this hypothesis, elements of the TGFβ signaling
pathway are commonly lost or defective in human cancers.12,13
*Correspondence to: David A. Foster; Department of Biological Sciences; Hunter
College of the City University of New York; 695 Park Avenue; New York, New York
10021 USA; Tel.: 212.772.4075; Email: [email protected]
Submitted: 04/28/08; Accepted: 04/28/08
This paper was translated into Chinese from its original publication in English.
Translated by: Beijing Xinglin Meditrans Center and Hua He on 05/23/08.
The Chinese version of this paper is published in: Ai Zheng(Chinese Journal
of Cancer), 27(8); http://www.cjcsysu.cn/cn/article.asp?id=14916
Previously published online as a Chinese Journal of Cancer E‑publication:
http://www.landesbioscience.com/journals/cjc/6193
180
mTOR has been implicated as sensor of nutritional sufficiency.14
Thus, mTOR activation may allow cells to proceed through G1
when there is access to the nutrients necessary to double in mass
prior to dividing. This hypothesis is consistent with the observa‑
tion that rapamycin leads to G1 cell cycle arrest and reduced cell
size.15 The cell cycle arrest induced by rapamycin is consistent with
a TGFβ arrest due to the stimulation of p27, which targets cyclin
E and its partner kinase—cyclin‑dependent kinase 2 (CDK2).
Thus, rapamycin would arrest cells in G1 at the point where cyclin
E‑CDK2 stimulates progression into S‑phase.16 We refer to this cyclin
E‑dependent checkpoint in G1 as a “cell growth checkpoint” that is
regulated by an mTOR‑dependent suppression of TGFβ signals. A
model for the mTOR control of cell cycle progression through this
late G1 checkpoint that is sensitive to nutritional ­sufficiency is shown
schematically in Figure 1.
We recently reported that suppression of mTOR led to a G1
cell cycle arrest in the human breast cancer cell line MDA‑MB‑231
and that this arrest was due to a de‑repression of TGFβ signaling.10
Massague and colleagues had reported previously that TGFβ
signaling was suppressed in this cell line.17 The suppression of
TGFβ signaling in these cells was due to elevated PLD activity,
which activates mTOR,18‑20 and suppresses TGFβ signaling.11
Importantly, if TGFβ was absent, rapamycin treatment resulted in
apoptosis rather than cell cycle arrest.10 The implication was that
the TGFβ‑mediated cell cycle arrest prevented apoptosis—or to
look at it from another perspective—rapamycin induces apoptosis if
cells get past the proposed cell growth checkpoint and progress into
S‑phase. This observation makes sense if you assume that mTOR
is critical for progression into and/or through S‑phase. Once cells
have made the commitment to replicate their DNA and divide,
any disruption in nutrient availability—as indicated by the lack of
mTOR activation (or repression by rapamycin)—could be disas‑
trous for completing the replication of DNA. Consequently, it is a
reasonable assumption that cells would choose apoptosis over arrest
at this point. This hypothesis was tested by synchronizing cells in
S‑phase and then treating with rapamycin in the presence of TGFβ.
As predicted, if cells progressed past the cell growth checkpoint into
S‑phase, rapamycin induced apoptosis.10 The effect of rapamycin on
cells in the presence and absence of TGFβ is shown schematically in
Figure 2. It is proposed that prior to the proposed cell growth point,
Chinese Journal of Cancer
2008; Vol. 27 Issue 8
Can defective TGFβ signaling be an Achilles heel in human cancer?
Figure 1. mTOR suppresses TGFβ signaling and G1 cell cycle arrest. It is
­proposed that mTOR‑mediated survival signals involve the suppression of
TGFβ signaling, which elevates p27Kip1 and blocks cyclin E‑CDK, which
is necessary for passage into S‑phase. We propose that this site in G1
­controlled by mTOR is a cell growth checkpoint in that mTOR is a sensor
of nutritional sufficiency. There is an apparent need for cancer cells to keep
mTOR activated and survival signals mediated by either PLD or PI3K to
­activate mTOR and thusly overriding this cell cycle checkpoint.
derivatives. This hypothesis was tested on three human cancer cell
lines with defects in TGFβ signaling, and as predicted, all three cell
lines were killed, rather than arrested by rapamycin.10 Thus, the
status of TGFβ signaling could be a critical factor for determining
whether rapamycin will be an effective and appropriate strategy for
­anti‑cancer therapeutic strategies.
The use of rapamycin in therapeutic strategies for targeting
human cancers has been widely discussed because it is well tolerated,
it is highly specific for mTOR, and because it targets survival signals
in cancer cells.4,24,25 The recent studies discussed in this perspective
suggest that rapamycin could be used to specifically target the large
number of human cancers with defects in TGFβ signaling. While
the loss of TGFβ signals in promotes cell cycle progression and
suppresses apoptosis,12 the loss of a TGFβ‑dependent G1 cell cycle
checkpoint may represent an Achilles heel for cancer cells by making
rapamycin a cytotoxic, rather than a cytostatic drug. Alternatively,
in cancers where TGFβ signaling is intact, strategies that suppress
TGFβ signaling could convert rapamycin from a cytostatic to a
cytotoxic drug.
Acknowledgements
This work described here was supported by grants from the
National Cancer Institute CA46677 and a SCORE grant from
the National Institutes of Health GM60654. Research Centers
in Minority Institutions award RR‑03037 from the National
Center for Research Resources of the National Institutes of Health,
which supports infrastructure and instrumentation in the Biological
Sciences Department at Hunter College, is also acknowledged.
References
Figure 2. Differential effects of rapamycin before and after the cell growth
checkpoint. In the presence of TGFβ, rapamycin treatment induces G1 cell
cycle arrest at a proposed cell growth checkpoint. However, if cells progress
past this point, they undergo apoptosis if mTOR is suppressed. If TGFβ sig‑
naling is compromised, then cells are not arrested by rapamycin and they
progress into a part of the cell cycle where mTOR is required. However,
in the absence of mTOR signals, which indicates nutritional sufficiency, an
apoptotic program is activated.
rapamycin induces cell cycle arrest—if TGFβ is present. However,
if cells get past this checkpoint, the lack of mTOR signals reveals a
nutritional deficiency, and since the cells have passed the checkpoint
for nutritional ­competence, the cells now undergo apoptosis.
An important implication from this study is that cells with defec‑
tive TGFβ signaling should respond to rapamycin by undergoing
apoptosis rather than cell cycle arrest. There are many tumors with
genetic defects in TGFβ signaling—particularly in the Smad4
gene,21 which localizes to a region of chromosome 18q where there
is considerable loss‑of‑heterozygosity. This is particularly common
in colon22 and pancreatic23 cancers. Thus, there are many cancers
that are good candidates for targeting with rapamycin or rapamycin
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