Hypoxia-Induced Autophagy Promotes Tumor Cell Survival and Adaptation to Antiangiogenic Treatment in Glioblastoma

Cancer Research - Tập 72 Số 7 - Trang 1773-1783 - 2012
Yu-Long Hu1, Michael DeLay1, Arman Jahangiri1, Annette M. Molinaro1, Samuel D. Rose1, W. Shawn Carbonell1, Manish K. Aghi1
1Authors' Affiliation: University of California at San Francisco (UCSF) Neurosurgery, San Francisco, California

Tóm tắt

Abstract Antiangiogenic therapy leads to devascularization that limits tumor growth. However, the benefits of angiogenesis inhibitors are typically transient and resistance often develops. In this study, we explored the hypothesis that hypoxia caused by antiangiogenic therapy induces tumor cell autophagy as a cytoprotective adaptive response, thereby promoting treatment resistance. Hypoxia-induced autophagy was dependent on signaling through the hypoxia-inducible factor-1α (HIF-1α)/AMPK pathway, and treatment of hypoxic cells with autophagy inhibitors caused a shift from autophagic to apoptotic cell death in vitro. In glioblastomas, clinically resistant to the VEGF-neutralizing antibody bevacizumab, increased regions of hypoxia and higher levels of autophagy-mediating BNIP3 were found when compared with pretreatment specimens from the same patients. When treated with bevacizumab alone, human glioblastoma xenografts showed increased BNIP3 expression and hypoxia-associated growth, which could be prevented by addition of the autophagy inhibitor chloroquine. In vivo targeting of the essential autophagy gene ATG7 also disrupted tumor growth when combined with bevacizumab treatment. Together, our findings elucidate a novel mechanism of resistance to antiangiogenic therapy in which hypoxia-mediated autophagy promotes tumor cell survival. One strong implication of our findings is that autophagy inhibitors may help prevent resistance to antiangiogenic therapy used in the clinic. Cancer Res; 72(7); 1773–83. ©2012 AACR.

Từ khóa


Tài liệu tham khảo

Jain, 2008, Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer, Nat Rev Cancer, 8, 309, 10.1038/nrc2346

Vredenburgh, 2007, Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma, Clin Cancer Res, 13, 1253, 10.1158/1078-0432.CCR-06-2309

Clark, 2012, Neurosurgical management and prognosis of patients with glioblastoma that progress during bevacizumab treatment, Neurosurgery, 70, 361, 10.1227/NEU.0b013e3182314f9d

Mazure, 2010, Hypoxia-induced autophagy: cell death or cell survival?, Curr Opin Cell Biol, 22, 177, 10.1016/j.ceb.2009.11.015

Tracy, 2007, BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy, Mol Cell Biol, 27, 6229, 10.1128/MCB.02246-06

Xie, 2007, Autophagosome formation: core machinery and adaptations, Nat Cell Biol, 9, 1102, 10.1038/ncb1007-1102

Boya, 2005, Inhibition of macroautophagy triggers apoptosis, Mol Cell Biol, 25, 1025, 10.1128/MCB.25.3.1025-1040.2005

Lum, 2005, Growth factor regulation of autophagy and cell survival in the absence of apoptosis, Cell, 120, 237, 10.1016/j.cell.2004.11.046

Sato, 2007, Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation, Cancer Res, 67, 9677, 10.1158/0008-5472.CAN-07-1462

Geng, 2008, The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. ‘Protein modifications: beyond the usual suspects’ review series, EMBO Rep, 9, 859, 10.1038/embor.2008.163

Kirkin, 2009, A role for ubiquitin in selective autophagy, Mol Cell, 34, 259, 10.1016/j.molcel.2009.04.026

Norden, 2008, Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence, Neurology, 70, 779, 10.1212/01.wnl.0000304121.57857.38

Paez-Ribes, 2009, Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis, Cancer Cell, 15, 220, 10.1016/j.ccr.2009.01.027

Wykoff, 2000, Hypoxia-inducible expression of tumor-associated carbonic anhydrases, Cancer Res, 60, 7075

Kamiyama, 2005, Anti-angiogenic effects of SN38 (active metabolite of irinotecan): inhibition of hypoxia-inducible factor 1 alpha (HIF-1alpha)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells, J Cancer Res Clin Oncol, 131, 205, 10.1007/s00432-004-0642-z

Eng, 2010, Ammonia derived from glutaminolysis is a diffusible regulator of autophagy, Sci Signal, 3, ra31, 10.1126/scisignal.2000911

Rzymski, Regulation of autophagy by ATF4 in response to severe hypoxia, Oncogene, 29, 4424, 10.1038/onc.2010.191

Pursiheimo, 2009, Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62, Oncogene, 28, 334, 10.1038/onc.2008.392

Mizushima, 2007, How to interpret LC3 immunoblotting, Autophagy, 3, 542, 10.4161/auto.4600

Satoo, 2009, The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy, EMBO J, 28, 1341, 10.1038/emboj.2009.80

Yeo, 2003, YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1, J Natl Cancer Inst, 95, 516, 10.1093/jnci/95.7.516

Mizushima, 2010, Methods in mammalian autophagy research, Cell, 140, 313, 10.1016/j.cell.2010.01.028

Yang, 2011, Pancreatic cancers require autophagy for tumor growth, Genes Dev, 25, 717, 10.1101/gad.2016111

Amaravadi, 2011, Principles and current strategies for targeting autophagy for cancer treatment, Clin Cancer Res, 17, 654, 10.1158/1078-0432.CCR-10-2634

Masiero, 2009, Autophagy is required to maintain muscle mass, Cell Metab, 10, 507, 10.1016/j.cmet.2009.10.008

Giatromanolaki, 2004, BNIP3 expression is linked with hypoxia-regulated protein expression and with poor prognosis in non-small cell lung cancer, Clin Cancer Res, 10, 5566, 10.1158/1078-0432.CCR-04-0076

Giatromanolaki, 2008, BNIP3 expression in endometrial cancer relates to active hypoxia inducible factor 1alpha pathway and prognosis, J Clin Pathol, 61, 217, 10.1136/jcp.2007.046680

Kanzawa, 2004, Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells, Cell Death Differ, 11, 448, 10.1038/sj.cdd.4401359

Apel, 2008, Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy, Cancer Res, 68, 1485, 10.1158/0008-5472.CAN-07-0562

Amaravadi, 2007, The roles of therapy-induced autophagy and necrosis in cancer treatment, Clin Cancer Res, 13, 7271, 10.1158/1078-0432.CCR-07-1595

Carew, 2007, Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance, Blood, 110, 313, 10.1182/blood-2006-10-050260

Bergers, 2008, Modes of resistance to anti-angiogenic therapy, Nat Rev Cancer, 8, 592, 10.1038/nrc2442

Winkler, 2004, Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases, Cancer Cell, 6, 553

Keunen, 2011, Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma, Proc Natl Acad Sci U S A, 108, 3749, 10.1073/pnas.1014480108

Pouyssegur, 2006, Hypoxia signalling in cancer and approaches to enforce tumour regression, Nature, 441, 437, 10.1038/nature04871

Sowter, 2001, HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors, Cancer Res, 61, 6669

Brown, 2004, Exploiting tumour hypoxia in cancer treatment, Nat Rev Cancer, 4, 437, 10.1038/nrc1367

Li, 2007, Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb, J Biol Chem, 282, 35803, 10.1074/jbc.M705231200

Bernardi, 2006, PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR, Nature, 442, 779, 10.1038/nature05029

Gwinn, 2008, AMPK phosphorylation of raptor mediates a metabolic checkpoint, Mol Cell, 30, 214, 10.1016/j.molcel.2008.03.003

Jung, 2009, ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery, Mol Biol Cell, 20, 1992, 10.1091/mbc.e08-12-1249

Bellot, 2009, Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains, Mol Cell Biol, 29, 2570, 10.1128/MCB.00166-09

Aghi, 2006, Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes, Cancer Res, 66, 9054, 10.1158/0008-5472.CAN-05-3759

Blouw, 2003, The hypoxic response of tumors is dependent on their microenvironment, Cancer Cell, 4, 133, 10.1016/S1535-6108(03)00194-6

Sotelo, 2006, Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial, Ann Intern Med, 144, 337, 10.7326/0003-4819-144-5-200603070-00008

Augustijns, 1992, Chloroquine levels in blood during chronic treatment of patients with rheumatoid arthritis, Eur J Clin Pharmacol, 42, 429, 10.1007/BF00280130

Thông tin
Thông tin xuất bản

Cancer Research

Tập 72 Số 7

1773-1783

Thông tin tác giả