Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis

Oncogene volume 30, pages 1855–1867 (2011)Cite this article

Subjects

Abstract

Hematopoietic cells normally require cell extrinsic signals to maintain metabolism and survival. In contrast, cancer cells can express constitutively active oncogenic kinases such as BCR-Abl that promote these processes independent of extrinsic growth factors. When cells receive insufficient growth signals or when oncogenic kinases are inhibited, glucose metabolism decreases and the self-digestive process of autophagy is elevated to degrade bulk cytoplasm and organelles. Although autophagy has been proposed to provide a cell-intrinsic nutrient supply for mitochondrial oxidative metabolism and to maintain cellular homeostasis through degradation of damaged organelles or protein aggregates, its acute role in growth factor deprivation or inhibition of oncogenic kinases remains poorly understood. We therefore developed a growth factor-dependent hematopoietic cell culture model in which autophagy can be acutely disrupted through conditional Cre-mediated excision of the autophagy-essential gene Atg3. Treated cells rapidly lost their ability to perform autophagy and underwent cell cycle arrest and apoptosis. Although Atg3 was essential for optimal upregulation of mitochondrial oxidative pathways in growth factor withdrawal, this metabolic contribution of autophagy did not appear critical for cell survival, as provision of exogenous pyruvate or lipids could not completely rescue Atg3 deficiency. Instead, autophagy suppressed a stress response that otherwise led to p53 phosphorylation and upregulation of p21 and the pro-apoptotic Bcl-2 family protein Puma. Importantly, BCR-Abl-expressing cells had low basal levels of autophagy, but were highly dependent on this process, and rapidly underwent apoptosis upon disruption of autophagy through Atg3 deletion or treatment with chemical autophagy inhibitors. This dependence on autophagy extended in vivo, as Atg3 deletion also prevented BCR-Abl-mediated leukemogenesis in a cell transfer model. Together these data demonstrate a critical role for autophagy to mitigate cell stress, and that cells expressing the oncogenic kinase BCR-Abl appear particularly dependent on autophagy for cell survival and leukemogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Altman BJ, Rathmell JC . (2009). Autophagy: not good OR bad, but good AND bad. Autophagy 5: 569–570.

    Article  PubMed  Google Scholar 

  • Altman BJ, Wofford JA, Zhao Y, Coloff JL, Ferguson EC, Wieman HL et al. (2009). Autophagy provides nutrients but can lead to chop-dependent induction of Bim to sensitize growth factor-deprived cells to apoptosis. Mol Biol Cell 20: 1180–1191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI et al. (2007). Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 117: 326–336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • An J, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI et al. (2004). Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 10: 268–274.

    Article  CAS  PubMed  Google Scholar 

  • Bellodi C, Lidonnici MR, Hamilton A, Helgason GV, Soliera AR, Ronchetti M et al. (2009). Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest 119: 1109–1123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernales S, McDonald KL, Walter P . (2006). Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4: e423.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A et al. (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171: 603–614.

    Article  PubMed  PubMed Central  Google Scholar 

  • Carew JS, Nawrocki ST, Kahue CN, Zhang H, Yang C, Chung L et al. (2007). Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood 110: 313–322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colell A, Ricci JE, Tait S, Milasta S, Maurer U, Bouchier-Hayes L et al. (2007). GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell 129: 983–997.

    Article  CAS  PubMed  Google Scholar 

  • Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR et al. (2006). DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126: 121–134.

    Article  CAS  PubMed  Google Scholar 

  • Darzynkiewicz Z, Juan G . (2001). Analysis of DNA content and BrdU incorporation. Curr Protoc Cytom Chapter 7: Unit 7 7.

    PubMed  Google Scholar 

  • DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB . (2008). The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11–20.

    Article  CAS  PubMed  Google Scholar 

  • Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G et al. (2006). Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10: 51–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edinger AL, Thompson CB . (2002). Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 13: 2276–2288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng Z, Zhang H, Levine AJ, Jin S . (2005). The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102: 8204–8209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  PubMed  Google Scholar 

  • Hoyer-Hansen M, Jaattela M . (2007). Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14: 1576–1582.

    Article  CAS  PubMed  Google Scholar 

  • Ishihara T, Hoshino T, Namba T, Tanaka K, Mizushima T . (2007). Involvement of up-regulation of PUMA in non-steroidal anti-inflammatory drug-induced apoptosis. Biochem Biophys Res Commun 356: 711–717.

    Article  CAS  PubMed  Google Scholar 

  • Iwata J, Ezaki J, Komatsu M, Yokota S, Ueno T, Tanida I et al. (2006). Excess peroxisomes are degraded by autophagic machinery in mammals. J Biol Chem 281: 4035–4041.

    Article  CAS  PubMed  Google Scholar 

  • Jacobs SR, Michalek RD, Rathmell JC . (2010). IL-7 is essential for homeostatic control of T cell metabolism in vivo. J Immunol 184: 3461–3469.

    Article  CAS  PubMed  Google Scholar 

  • Jin S, DiPaola RS, Mathew R, White E . (2007). Metabolic catastrophe as a means to cancer cell death. J Cell Sci 120: 379–383.

    Article  CAS  PubMed  Google Scholar 

  • Jin S, White E . (2007). Role of autophagy in cancer: management of metabolic stress. Autophagy 3: 28–31.

    Article  CAS  PubMed  Google Scholar 

  • Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E et al. (2008). The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ 15: 1712–1722.

    Article  CAS  PubMed  Google Scholar 

  • Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S et al. (2007). Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 21: 1621–1635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karawajew L, Rhein P, Czerwony G, Ludwig WD . (2005). Stress-induced activation of the p53 tumor suppressor in leukemia cells and normal lymphocytes requires mitochondrial activity and reactive oxygen species. Blood 105: 4767–4775.

    Article  CAS  PubMed  Google Scholar 

  • Kharas MG, Fruman DA . (2005). ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors. Cancer Res 65: 2047–2053.

    Article  CAS  PubMed  Google Scholar 

  • Kim I, Rodriguez-Enriquez S, Lemasters JJ . (2007). Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462: 245–253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kiyono K, Suzuki HI, Matsuyama H, Morishita Y, Komuro A, Kano MR et al. (2009). Autophagy is activated by TGF-beta and potentiates TGF-beta-mediated growth inhibition in human hepatocellular carcinoma cells. Cancer Res 69: 8844–8852.

    Article  CAS  PubMed  Google Scholar 

  • Kurz EU, Lees-Miller SP . (2004). DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair (Amst) 3: 889–900.

    Article  CAS  Google Scholar 

  • Lainez S, Valente P, Ontoria-Oviedo I, Estevez-Herrera J, Camprubi-Robles M, Ferrer-Montiel A et al. (2010). GABAA receptor associated protein (GABARAP) modulates TRPV1 expression and channel function and desensitization. FASEB J 24: 1958–1970.

    Article  CAS  PubMed  Google Scholar 

  • Legesse-Miller A, Sagiv Y, Glozman R, Elazar Z . (2000). Aut7p, a soluble autophagic factor, participates in multiple membrane trafficking processes. J Biol Chem 275: 32966–32973.

    Article  CAS  PubMed  Google Scholar 

  • Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H et al. (1999). Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402: 672–676.

    Article  CAS  PubMed  Google Scholar 

  • Liu B, Chen Y, St Clair DK . (2008). ROS and p53: a versatile partnership. Free Radic Biol Med 44: 1529–1535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lomonaco SL, Finniss S, Xiang C, Decarvalho A, Umansky F, Kalkanis SN et al. (2009). The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells. Int J Cancer 125: 717–722.

    Article  CAS  PubMed  Google Scholar 

  • Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T et al. (2005a). Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120: 237–248.

    Article  CAS  PubMed  Google Scholar 

  • Lum JJ, DeBerardinis RJ, Thompson CB . (2005b). Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 6: 439–448.

    Article  CAS  PubMed  Google Scholar 

  • Luo J, Solimini NL, Elledge SJ . (2009). Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136: 823–837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mason EF, Zhao Y, Goraksha-Hicks P, Coloff JL, Gannon H, Jones SN et al. (2010). Aerobic glycolysis suppresses p53 activity to provide selective protection from apoptosis upon loss of growth signals or inhibition of BCR-Abl. Cancer Res 70: 8066–8076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY et al. (2009). Autophagy suppresses tumorigenesis through elimination of p62. Cell 137: 1062–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K et al. (2007). Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 21: 1367–1381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Modi H, McDonald T, Chu S, Yee JK, Forman SJ, Bhatia R . (2007). Role of BCR/ABL gene-expression levels in determining the phenotype and imatinib sensitivity of transformed human hematopoietic cells. Blood 109: 5411–5421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niizuma K, Endo H, Chan PH . (2009). Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J Neurochem 109 (Suppl 1): 133–138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H et al. (2007). p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282: 24131–24145.

    Article  CAS  PubMed  Google Scholar 

  • Plas DR, Talapatra S, Edinger AL, Rathmell JC, Thompson CB . (2001). Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J Biol Chem 276: 12041–12048.

    Article  CAS  PubMed  Google Scholar 

  • Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND et al. (2007). ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129: 1337–1349.

    Article  CAS  PubMed  Google Scholar 

  • Raff MC . (1992). Social controls on cell survival and cell death. Nature 356: 397–400.

    Article  CAS  PubMed  Google Scholar 

  • Rathmell JC, Vander Heiden MG, Harris MH, Frauwirth KA, Thompson CB . (2000). In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol Cell 6: 683–692.

    Article  CAS  PubMed  Google Scholar 

  • Ren JH, He WS, Nong L, Zhu QY, Hu K, Zhang RG et al. (2010). Acquired cisplatin resistance in human lung adenocarcinoma cells is associated with enhanced autophagy. Cancer Biother Radiopharm 25: 75–80.

    Article  CAS  PubMed  Google Scholar 

  • Sagiv Y, Legesse-Miller A, Porat A, Elazar Z . (2000). GATE-16, a membrane transport modulator, interacts with NSF and the Golgi v-SNARE GOS-28. EMBO J 19: 1494–1504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seglen PO, Gordon PB . (1982). 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci USA 79: 1889–1892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M et al. (2009). Autophagy regulates lipid metabolism. Nature 458: 1131–1135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solomon VR, Lee H . (2009). Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol 625: 220–233.

    Article  CAS  PubMed  Google Scholar 

  • Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB . (2001). Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 21: 5899–5912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wan G, Zhaorigetu S, Liu Z, Kaini R, Jiang Z, Hu CA . (2008). Apolipoprotein L1, a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death. J Biol Chem 283: 21540–21549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weidberg H, Shvets E, Shpilka T, Shimron F, Shinder V, Elazar Z . (2010). LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. EMBO J 29: 1792–1802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wieman HL, Wofford JA, Rathmell JC . (2007). Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell 18: 1437–1446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yue Z, Jin S, Yang C, Levine AJ, Heintz N . (2003). Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 100: 15077–15082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Altman BJ, Coloff JL, Herman CE, Jacobs SR, Wieman HL et al. (2007). Glycogen synthase kinase 3alpha and 3beta mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1. Mol Cell Biol 27: 4328–4339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zinkel SS, Hurov KE, Ong C, Abtahi FM, Gross A, Korsmeyer SJ . (2005). A role for proapoptotic BID in the DNA-damage response. Cell 122: 579–591.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH R01 CA123350 (JCR), Leukemia and Lymphoma Society Scholar Award (JCR), Alex's Lemonade Stand (JCR) and Gabrielle's Angel Foundation for Cancer Research (JCR). JCR is the Bernard Osher Fellow of the American Asthma Foundation. EFM is supported by NIH F30 HL094044 and RDM is supported by the Irvington Institute Postdoctoral Fellowship from the Cancer Research Institute.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

    B J Altman, S R Jacobs, E F Mason, R D Michalek, A N MacIntyre, J L Coloff, O Ilkayeva & J C Rathmell

  2. Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC, USA

    O Ilkayeva & J C Rathmell

  3. Department of Immunology, Duke University Medical Center, Durham, NC, USA

    W Jia, Y-W He & J C Rathmell

Authors
  1. B J Altman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S R Jacobs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E F Mason
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R D Michalek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A N MacIntyre
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J L Coloff
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. O Ilkayeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y-W He
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J C Rathmell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J C Rathmell.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Altman, B., Jacobs, S., Mason, E. et al. Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis. Oncogene 30, 1855–1867 (2011). https://doi.org/10.1038/onc.2010.561

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.561

Keywords

This article is cited by

Search

Advanced search

Quick links