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• W2079605616 abstract "In this issue of Molecular Cell, Elgendy et al. suggest that Ras-induced autophagy may kill tumor cells on the verge of oncogenic transformation, providing a contrast to recent reports indicating that autophagy is required for optimal growth of Ras-driven cancers. In this issue of Molecular Cell, Elgendy et al. suggest that Ras-induced autophagy may kill tumor cells on the verge of oncogenic transformation, providing a contrast to recent reports indicating that autophagy is required for optimal growth of Ras-driven cancers. When cancer cells die in response to adverse conditions such as hypoxia or chemotherapy, they often manifest signs of macroautophagy (which we refer to as “autophagy”). During autophagy, two-membraned vesicles called autophagosomes sequester portions of the cytoplasm. Whether autophagy results in so-called “autophagic cell death” or if it instead reflects a desperate attempt by cells to cope with stress by recycling damaged organelles is a subject of debate (Kroemer and Levine, 2008Kroemer G. Levine B. Nat. Rev. Mol. Cell Biol. 2008; 9: 1004-1010Crossref PubMed Scopus (1063) Google Scholar). In this issue of Molecular Cell, Elgendy et al., 2011Elgendy M. Sheridan C. Brumatti G. Martin S.J. Mol. Cell. 2011; 42 (this issue): 23-35Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar provide a convincing example of “autophagic cell death.” Using a human ovarian surface epithelial (HOSE) cell line in which oncogenic H-RasV12 can be induced with tetracycline, the authors reveal a caspase-independent cell death pathway that relies on the activation of stress kinases (particularly MEK and ERK) and the subsequent upregulation of both Beclin-1 and Noxa that eventually leads to cell death. This death lacked hallmarks of apoptosis, such as chromatin condensation, yet occurs with massive autophagic vacuolization. Knockdown of both Beclin-1 and Noxa as well as depletion of essential autophagy proteins such as Atg5 and Atg7 prevented autophagy, avoided cell death, and restored the clonogenic survival of HOSE cells that otherwise would be lost upon activation of H-RasV12. Very similar results suggesting the occurrence of autophagic death mediated by Atg5, Atg7, Beclin-1, and Noxa were obtained in MCF7 breast cancer and human umbilical vein endothelial cells acutely transfected with H-RasV12 (Elgendy et al., 2011Elgendy M. Sheridan C. Brumatti G. Martin S.J. Mol. Cell. 2011; 42 (this issue): 23-35Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar). How can this be explained in mechanistic terms? Beclin-1 usually interacts with antiapoptotic proteins of the Bcl-1 family such as Bcl-2, Bcl-XL, and Mcl-1. These proteins inhibit Beclin-1-mediated activation of the VPS34 phosphatidylinositol 3-kinase that is responsible for the synthesis of phosphatidylinositol 3-phosphate, which in turn is essential for autophagy. The inhibitory interaction between Beclin-1 and Bcl-2-like proteins is mediated by the presence of a BH3 domain in Beclin-1 that interacts with the BH3-binding groove of Bcl-2, Bcl-XL, or Mcl-1 (Maiuri et al., 2009Maiuri M.C. Tasdemir E. Criollo A. Morselli E. Vicencio J.M. Carnuccio R. Kroemer G. Cell Death Differ. 2009; 16: 87-93Crossref PubMed Scopus (327) Google Scholar). Upon H-RasV12 activation, Noxa, which also possesses a BH3 domain, competitively displaces Beclin-1 from its inhibitory interaction with Mcl-1, presumably because Noxa binds to Mcl-1 with a much higher affinity than Beclin-1 (Elgendy et al., 2011Elgendy M. Sheridan C. Brumatti G. Martin S.J. Mol. Cell. 2011; 42 (this issue): 23-35Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar). Freed from Mcl-1, Beclin-1 can promote autophagy (Figure 1A ). The finding that oncogenic H-RasV12 can kill tumor cells supports previous reports indicating that Ras can trigger autophagy and cell death in neuroblastoma, perhaps explaining spontaneous tumor regression in this pediatric cancer (Kitanaka et al., 2002Kitanaka C. Kato K. Ijiri R. Sakurada K. Tomiyama A. Noguchi K. Nagashima Y. Nakagawara A. Momoi T. Toyoda Y. et al.J. Natl. Cancer Inst. 2002; 94: 358-368Crossref PubMed Scopus (89) Google Scholar). However, these results seem to contrast with three other recent reports indicating that autophagy is required for the optimal growth of tumor cells transformed with oncogenic H-RasV12 or K-RasV12 (Guo et al., 2011Guo J.Y. Chen H.Y. Mathew R. Fan J. Strohecker A.M. Karsli-Uzunbas G. Kamphorst J.J. Chen G. Lemons J.M. Karantza V. et al.Genes Dev. 2011; 25: 460-470Crossref PubMed Scopus (831) Google Scholar, Kim et al., 2011Kim M.J. Woo S.J. Yoon C.H. Lee J.S. An S. Choi Y.H. Hwang S.G. Yoon G. Lee S.J. J. Biol. Chem. 2011; (in press. Published online February 7, 2011)https://doi.org/10.1074/jbc.M110.138958Crossref Scopus (161) Google Scholar, Lock et al., 2011Lock R. Roy S. Kenific C.M. Su J.S. Salas E. Ronen S.M. Debnath J. Mol. Biol. Cell. 2011; 22: 165-178Crossref PubMed Scopus (323) Google Scholar). In these studies, H-RasV12 was more efficient in stimulating contact-independent growth of wild-type mouse embryonic fibroblasts (MEFs) than autophagy-deficient MEFs lacking the Atg3, Atg5, and Atg7 genes. Furthermore, knockdown of ATG7 or ATG12 reduced soft agar growth of human epithelial cancer cells that either express pre-existing Ras mutations (like MDA-MB-231 cells) or were manipulated to express H-RasV12 (like MCF10A cells) (Lock et al., 2011Lock R. Roy S. Kenific C.M. Su J.S. Salas E. Ronen S.M. Debnath J. Mol. Biol. Cell. 2011; 22: 165-178Crossref PubMed Scopus (323) Google Scholar). MCF10A cells transformed with oncogenic K-RasV12 also manifested the reactive oxygen species (ROS)- and stress kinase (in particular, JNK)-dependent induction of the ATG5 and ATG7 proteins. And knockdown of ATG5 or ATG7 prevented K-RasV12-induced autophagy, reduced soft agar transformation, and attenuated tumor growth on immunodeficient mice (Kim et al., 2011Kim M.J. Woo S.J. Yoon C.H. Lee J.S. An S. Choi Y.H. Hwang S.G. Yoon G. Lee S.J. J. Biol. Chem. 2011; (in press. Published online February 7, 2011)https://doi.org/10.1074/jbc.M110.138958Crossref Scopus (161) Google Scholar). Similarly, in a panel of human carcinoma cell lines, those lines carrying activating mutations of Ras had high baseline autophagic activity, and some of these cell lines were killed by knockdown of Atg5 or Atg7 (Guo et al., 2011Guo J.Y. Chen H.Y. Mathew R. Fan J. Strohecker A.M. Karsli-Uzunbas G. Kamphorst J.J. Chen G. Lemons J.M. Karantza V. et al.Genes Dev. 2011; 25: 460-470Crossref PubMed Scopus (831) Google Scholar). The introduction of H-RasV12 or K-RasV12 into immortal, nontumorigenic baby mouse kidney epithelial cells (iBMKs) also stimulated baseline autophagy. Ras-expressing wild-type iBMKs were more resistant to the induction of apoptosis by starvation (culture in serum-free and nutrient-free medium) or metabolic stress (glucose deprivation and 1% oxygen) than autophagy-deficient (atg5−/−, atg7−/−, or sqtm1−/−) iBMKs. Ras-transformed atg5−/−, atg7−/−, and sqtm1−/− iBMKs formed smaller tumors than their autophagy-competent controls, and these autophagy-deficient tumors displayed signs of cellular dysfunction and apoptosis (Guo et al., 2011Guo J.Y. Chen H.Y. Mathew R. Fan J. Strohecker A.M. Karsli-Uzunbas G. Kamphorst J.J. Chen G. Lemons J.M. Karantza V. et al.Genes Dev. 2011; 25: 460-470Crossref PubMed Scopus (831) Google Scholar). Altogether, these results underscore the capacity of oncogenic Ras to induce autophagy, in accord with the findings of the Martin group (Elgendy et al., 2011Elgendy M. Sheridan C. Brumatti G. Martin S.J. Mol. Cell. 2011; 42 (this issue): 23-35Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar). Yet they also indicate that optimal growth of transformed cells in vivo or in stress conditions in vitro requires autophagy (Figure 1B). The capacity of autophagy to sustain the growth of transformed cells appears counterintuitive, at least at first glance, because one would expect that an enhanced cellular catabolism should negatively impact on anabolic reactions that are required for the growth and multiplication of cancer cells. However, there may be an indirect link. Ras-induced so-called “oncogenic stress” can lead, through an as yet poorly defined mechanism, to the overproduction of ROS, which in turn damages mitochondria. In these conditions, autophagy may prevent a major respiratory chain dysfunction because it assures the preferential elimination of dysfunctional organelles, the quality control through “mitophagy.” Accordingly, Ras-transformed, autophagy-competent cells exhibited a preserved mitochondrial ultrastructure and function, with a more efficient oxidative phosphorylation and a higher flux of tricarboxylate acid (TCA) metabolites than Ras-transformed autophagy-deficient cells (Guo et al., 2011Guo J.Y. Chen H.Y. Mathew R. Fan J. Strohecker A.M. Karsli-Uzunbas G. Kamphorst J.J. Chen G. Lemons J.M. Karantza V. et al.Genes Dev. 2011; 25: 460-470Crossref PubMed Scopus (831) Google Scholar). These results suggest that the mitochondrial conversion of pyruvate and/or fatty acids into acetyl-CoA and citrate is reduced in the context of disabled autophagy. Accordingly, the improved anchorage-independent growth of Ras-transformed, autophagy-competent cells has been correlated with an improved glycolytic capacity (Lock et al., 2011Lock R. Roy S. Kenific C.M. Su J.S. Salas E. Ronen S.M. Debnath J. Mol. Biol. Cell. 2011; 22: 165-178Crossref PubMed Scopus (323) Google Scholar). How is it possible to resolve the apparently contradictory observations that oncogenic Ras can stimulate Beclin-1- and Atg5-dependent cell death, yet Ras-transformed tumors require autophagy for their optimal growth? Obviously, there are multiple differences in experimental details between the studies. First, the studies used rather distinct cell lines, implying possible cell context-dependent differences. Second, the Martin group relied on a tetracycline-inducible construct or acute transfections to provoke expression of oncogenic Ras, while all the other studies involved the antibiotic selection of cells that express Ras together with the antibiotic resistance cassette. These differences in experimental design may have a major impact on the final results. Acutely induced Ras expression could reflect the very first phase of transformation, when an oncogenic mutation in Ras has just been acquired and drives oncogenic stress. This acute Ras expression may stimulate intrinsic cellular pathways that abort malignant transformation either by an irreversible cell cycle arrest (senescence) or by cell death. Indeed, Ras can trigger senescence and cell death, and essential autophagy proteins have been implicated in both these processes (Elgendy et al., 2011Elgendy M. Sheridan C. Brumatti G. Martin S.J. Mol. Cell. 2011; 42 (this issue): 23-35Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar, Young et al., 2009Young A.R. Narita M. Ferreira M. Kirschner K. Sadaie M. Darot J.F. Tavaré S. Arakawa S. Shimizu S. Watt F.M. Narita M. Genes Dev. 2009; 23: 798-803Crossref PubMed Scopus (703) Google Scholar), consistent with prior reports that autophagy acts as a tumor suppressive mechanism (Mathew and White, 2011Mathew R. White E. Curr. Opin. Genet. Dev. 2011; 21: 113-119Crossref PubMed Scopus (179) Google Scholar). Indeed, many oncogenic events lead to an at least transient suppression in autophagy that may favor genomic instability and hence accelerate tumorigenesis (Maiuri et al., 2009Maiuri M.C. Tasdemir E. Criollo A. Morselli E. Vicencio J.M. Carnuccio R. Kroemer G. Cell Death Differ. 2009; 16: 87-93Crossref PubMed Scopus (327) Google Scholar). In stark contrast, after selection for stable expression of oncogenic Ras by antibiotic selection, only those cells that have overcome oncogenic stress (and hence tolerate Ras) would be available for further characterization. Such cells, which may represent a later step in oncogenesis, then must activate the autophagic program to cope with the specific metabolic needs imposed by aberrant growth in conditions of metabolic stress or by the depletion of essential survival signals (Figure 1C). Further work is now needed to resolve the disparate findings. And still other important questions remain. As it stands, there is little doubt that even unmutated Ras can stimulate homeostatic autophagy under physiological ER stress (Wu et al., 2010Wu R.F. Ma Z. Liu Z. Terada L.S. Mol. Cell. Biol. 2010; 30: 3553-3568Crossref PubMed Scopus (169) Google Scholar). But are there distinct, context-dependent pathways through which oncogenic Ras can trigger cytocidal versus cytoprotective autophagy? Moreover, even though some autophagy-relevant proteins appear indispensable for killing cells that are on the verge of oncogenic transformation by Ras, it remains to be proven that it is autophagy—as a process—that kills the cells. As it stands, it is still possible that Atg5, Atg7, and Beclin-1 are involved in autophagy-unrelated mechanisms that ultimately lead to cell death. Oncogenic Ras-Induced Expression of Noxa and Beclin-1 Promotes Autophagic Cell Death and Limits Clonogenic SurvivalElgendy et al.Molecular CellFebruary 24, 2011In BriefDeregulated oncogenes such as MYC and RAS are typically insufficient to transform cells on their own due to the activation of pathways that restrain proliferation. Previous studies have shown that oncogenic H-Ras can induce proliferative arrest or senescence, depending on the cellular context. Here, we show that deregulated H-Ras activity can also lead to caspase-independent cell death with features of autophagy. Ras-induced autophagy was associated with upregulation of the BH3-only protein Noxa as well as the autophagy regulator Beclin-1. Full-Text PDF Open Archive" @default.
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• W2079605616 title "Autophagy in Ras-Induced Malignant Transformation: Fatal or Vital?" @default.
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