Autophagic flux determines cell death and survival in response to Apo2L/TRAIL (dulanermin)

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• 作者：Kamini Singh (17) (24)
  Arishya Sharma (17) (22)
  Maria C Mir (18)
  Judith A Drazba (19)
  Warren D Heston (17)
  Cristina Magi-Galluzzi (18) (20)
  Donna Hansel (18) (25)
  Brian P Rubin (18) (21)
  Eric A Klein (20)
  Alexandru Almasan (17) (23)
  
  17. Department of Cancer Biology ; Lerner Research Institute ; Cleveland Clinic ; Cleveland ; OH ; 44195 ; USA
  24. Memorial Sloan-Kettering Cancer Center ; 417 E68th Street ; New York ; NY ; 10065 ; USA
  22. Department of Biological ; Geological ; and Environmental Science ; Cleveland State University ; Cleveland ; OH ; USA
  18. Department of Anatomic Pathology ; Taussig Cancer Institute ; Cleveland Clinic ; Cleveland ; OH ; 44195 ; USA
  19. Imaging Core ; Lerner Research Institute ; Cleveland Clinic ; Cleveland ; OH ; 44195 ; USA
  20. Glickman Urological and Kidney Institute ; Cleveland Clinic ; Cleveland ; OH ; 44195 ; USA
  25. Department of Pathology ; University of California ; San Diego ; 9500 Gilman Drive ; La Jolla ; CA ; 92093 ; USA
  21. Department of Molecular Genetics ; Lerner Research Institute ; Cleveland Clinic Cleveland ; Cleveland ; OH ; 44195 ; USA
  23. Department of Radiation Oncology ; Taussig Cancer Institute ; Cleveland Clinic ; 9500 Euclid Avenue ; Cleveland ; OH ; 44195 ; USA
  
• 关键词：Autophagy ; p62/SQSTM1 ; Caspase ; 8 ; Prostate cancer ; Apo2L/TRAIL ; Dulanermin
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：1,774 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

Background Macroautophagy is a catabolic process that can mediate cell death or survival. Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment (TR) is known to induce autophagy. Here we investigated whether SQSTM1/p62 (p62) overexpression, as a marker of autophagic flux, was related to aggressiveness of human prostate cancer (PCa) and whether autophagy regulated the treatment response in sensitive but not resistant PCa cell lines. Methods Immunostaining and immunoblotting analyses of the autophagic markers p62 [in PCa tissue microarrays (TMAs) and PCa cell lines] and LC3 (in PCa cell lines), transmission electron microscopy, and GFP-mCherry-LC3 were used to study autophagy induction and flux. The effect of autophagy inhibition using pharmacologic (3-methyladenine and chloroquine) and genetic [(short hairpin (sh)-mediated knock-down of ATG7 and LAMP2) and small interfering (si)RNA-mediated BECN1 knock-down] approaches on TR-induced cell death was assessed by clonogenic survival, sub-G1 DNA content, and annexinV/PI staining by flow cytometry. Caspase-8 activation was determined by immunoblotting. Results We found that increased cytoplasmic expression of p62 was associated with high-grade PCa, indicating that autophagy signaling might be important for survival in high-grade tumors. TR-resistant cells exhibited high autophagic flux, with more efficient clearance of p62-aggregates in four TR-resistant PCa cell lines: C4-2, LNCaP, DU145, and CWRv22.1. In contrast, autophagic flux was low in TR-sensitive PC3 cells, leading to accumulation of p62-aggregates. Pharmacologic (chloroquine or 3-methyladenine) and genetic (shATG7 or shLAMP2) inhibition of autophagy led to cell death in TR-resistant C4-2 cells. shATG7-expressing PC3 cells, were less sensitive to TR-induced cell death whereas those shLAMP2-expressing were as sensitive as shControl-expressing PC3 cells. Inhibition of autophagic flux using chloroquine prevented clearance of p62 aggregates, leading to caspase-8 activation and cell death in C4-2 cells. In PC3 cells, inhibition of autophagy induction prevented p62 accumulation and hence caspase-8 activation. Conclusions We show that p62 overexpression correlates with advanced stage human PCa. Pharmacologic and genetic inhibition of autophagy in PCa cell lines indicate that autophagic flux can determine the cellular response to TR by regulating caspase-8 activation. Thus, combining various autophagic inhibitors may have a differential impact on TR-induced cell death.