Adenovirus expressing dual c-Met-specific shRNA exhibits potent antitumor effect through autophagic cell death accompanied by senescence-like phenotypes in glioblastoma cells
- Authors
- Lee, Jung-Sun; Oh, Eonju; Yoo, Ji Young; Choi, Kyeong Sook; Yoon, Mi Jin; Yun, Chae-Ok
- Issue Date
- Feb-2015
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- adenovirus; autophagic cell death; cancer gene therapy; c-Met; short hairpin RNA (shRNA)
- Citation
- ONCOTARGET, v.6, no.6, pp.4051 - 4065
- Indexed
- SCIE
SCOPUS
- Journal Title
- ONCOTARGET
- Volume
- 6
- Number
- 6
- Start Page
- 4051
- End Page
- 4065
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/25654
- DOI
- 10.18632/oncotarget.3018
- ISSN
- 1949-2553
- Abstract
- c-Met, a cognate receptor tyrosine kinase of hepatocyte growth factor, is overexpressed and/or mutated in number of tumors. Therefore, abrogation of c-Met signaling may serve as potential therapeutic targets. In this study, we generated Ads expressing single shRNA specific to c-Met (shMet) (dl/shMet4 and dl/shMet5) or dual shRNAs specific to c-Met (dl/shMet4+ 5); and examined the therapeutic potential of these newly engineered Ads in targeting c-Met, and delineated their mechanism of action in vitro and in vivo. Ads expressing shMet induced knock-down in c-Met, and phenotypically resulted in autophagy-like features including appearance of membranousvacuoles, formation of acidic vesicular organelles, and cleavage and recruitment of microtubule-associated protein1 light chain 3 to autophagosomes. Ads expressing shMet also suppressed Akt phosphorylation and increased number of senescence-related gene products including SM22, TGase II, and PAI-1. These changes resulted in inhibition of cell proliferation and G(2)/M arrest of U343 cells. In vivo, intratumoral injection with dl/shMet4+ 5 resulted in a significant reduction of tumor growth with corresponding increasing overall survival. Histopathological analysis of these treated tumors revealed that Atg5 was highly up-regulated, indicating the therapeutic induction of autophagy. In sum, these results reveal that autophagic cell death induced by shMet-expressing Ads provide a novel strategy for targeting c-Met-expressing tumors through non-apoptotic mechanism of cell death.
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