title: A role of Rab7 in stabilizing EGFR-Her2 and in sustaining Akt survival signal.
abstract: Rab7 plays an important role in regulating endocytic traffic. In view of an emerging role of membrane traffic in signaling and diseases, we have examined the possible role of Rab7 in oncogenesis. The role of Rab7 was investigated using shRNA-mediated knockdown in A431 and MCF7 cancer cells. To our surprise, Rab7 knockdown effectively suppressed anchorage-independent growth of cancer cells in soft agar. Anoikis (matrix-detachment triggered apoptosis) was enhanced, while the level of phosphorylated (active) Akt (which is a key survival factor) was significantly reduced. Also intriguing was the observation that EGFR and Her2 levels were significantly reduced when Rab7 was knocked-down. More robust reduction of EGFR and Her2 levels was observed when knocked-down cells were treated with HSP90 inhibitor geldanamycin (GA). Low concentration of GA (50-100 nm)-induced apoptosis of the Rab7 knocked-down cells but not control cells, suggesting that Rab7 and HSP90 together contribute to the optimal stability of EGFR and Her2 as well as to protect cancer cells from apoptosis. Rab7 seems to protect EGFR and Her2 from proteosome-mediated degradation. These results suggest that Rab7 is likely involved in protecting EGFR and Her2 from being degraded by the proteosome and in maintaining optimal Akt survival signal (especially during cell detachment or when HSP90 is inhibited). Rab7 is potentially a novel target for combinatory therapy with Hsp90 inhibitors.
authors.affiliation: School of Pharmaceutical Sciences, Institute for Biomedical Research, Xiamen University, Fujian, China. xmuibrwtl@xmu.edu.cn
authors.forename: Tuanlao
authors.initials: T
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Zexu
authors.initials: Z
authors.lastname: Ma
authors.forename: Ke
authors.initials: K
authors.lastname: Guo
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
mesh_terms: D000818:Animals; D023102:Anoikis; D017209:Apoptosis; D016227:Benzoquinones / Q000494:pharmacology; D049109:Cell Proliferation; D002470:Cell Survival; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D005822:Genetic Vectors; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D016086:Lentivirus / Q000235:genetics; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014161:Transduction, Genetic; D047368:Tumor Burden; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007976:Leupeptins; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020691:rab GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C001277:geldanamycin