Kallikrein-related peptidase 6 induces chemotherapeutic resistance by attenuating auranofin-induced cell death through activation of autophagy in gastric cancer
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Tae Woo Kim1,2,*, Seon-Jin Lee1,2,*, Jong-Tae Kim1, Sun Jung Kim3, Jeong-Ki Min4, Kwang-Hee Bae5, Haiyoung Jung1, Bo-Yeon Kim6, Jong-Seok Lim7, Young Yang7, Do-Young Yoon8, Yong-Kyung Choe1, Hee Gu Lee1,2
1Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
2Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Korea
3Department of Life Science, Dongguk University-Seoul, Seoul, Republic of Korea
4Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
5Research Center for Metabolic Regulation, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
6World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Republic of Korea
7Department of Biological Sciences, Sookmyung Women’s University, Seoul, Republic of Korea
8Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea
*These authors have contributed equally to this work
Hee Gu Lee, email: firstname.lastname@example.org
Yong-Kyung Choe, email: email@example.com
Keywords: kallikrein-related peptidase 6, autophagy, auranofin, cell death, chemoresistance
Received: April 14, 2016 Accepted: October 14, 2016 Published: November 15, 2016
Kallikrein-related peptidase 6 (KLK6) is a biomarker of gastric cancer associated with poor prognosis. Mechanisms by which KLK6 could be exploited for chemotherapeutic use are unclear. We evaluated auranofin (AF), a compound with cytotoxic effects, in KLK6-deficient cells, and we investigated whether KLK6 expression induces autophagy and acquisition of drug resistance in gastric cancer. Using cultured human cells and a mouse xenograft model, we investigated how KLK6 affects antitumor-reagent-induced cell death and autophagy. Expression levels of KLK6, p53, and autophagy marker LC3B were determined in gastric cancer tissues. We analyzed the effects of knockdown/overexpression of KLK6, LC3B, and p53 on AF-induced cell death in cancer cells. Increased KLK6 expression in human gastric cancer tissues and cells inhibited AF-induced cell motility due to increased autophagy and p53 levels. p53 dependent induction of KLK6 expression increased autophagy and drug resistance, whereas KLK6 silencing decreased the autophagy level and increased drug sensitivity. During AF-induced cell death, KLK6 and LC3B colocalized to autophagosomes, associated with p53, and were then trafficked to the cytosol. In the xenograft model of gastric cancer, KLK6 expression decreased AF-induced cell death and KLK6-induced autophagy increased AF resistance. Taken together, the data suggest that the induction of autophagic processes through KLK6 expression may increase acquisition of resistance to AF. Our findings may contribute to a new paradigm for tumor therapeutics.
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