Oncotarget

Research Papers:

Adenovirus expressing dual c-Met-specific shRNA exhibits potent antitumor effect through autophagic cell death accompanied by senescence-like phenotypes in glioblastoma cells

Jung-Sun Lee _, Eonju Oh, Ji Young Yoo, Kyeong Sook Choi, Mi Jin Yoon and Chae-Ok Yun

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Oncotarget. 2015; 6:4051-4065. https://doi.org/10.18632/oncotarget.3018

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Abstract

Jung-Sun Lee1,*, Eonju Oh3,*, Ji Young Yoo1, Kyeong Sook Choi2, Mi Jin Yoon2, Chae-Ok Yun3

1Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea

2Department of Molecular Science & Technology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea

3Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea

*These authors have contributed equally to this work

Correspondence to:

Chae-Ok Yun, e-mail: chaeok@hanyang.ac.kr

Keywords: adenovirus, autophagic cell death, cancer gene therapy, c-Met, short hairpin RNA (shRNA)

Received: July 15, 2014     Accepted: December 30, 2014     Published: February 17, 2015

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 G2/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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