Induction of endoplasmic reticulum stress and mitochondrial dysfunction dependent apoptosis signaling pathway in human renal cancer cells by norcantharidin
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Min-Hua Wu1,2, Hui-Ling Chiou3, Chu-Liang Lin4, Ching-Yi Lin5, Shun-Fa Yang1,6 and Yi-Hsien Hsieh4,7,8
1Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
2Department of Laboratory, Chung-Kang Branch, Cheng-Ching General Hospital, Taichung, Taiwan
3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
4Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
5Division Of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
6Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
7Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
8Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
Shun-Fa Yang, email: [email protected]
Yi-Hsien Hsieh, email: [email protected]
Keywords: norcantharidin; apoptosis; renal cancer cells; mitochondrial depolarization; endoplasmic reticulum
Received: September 07, 2017 Accepted: November 16, 2017 Published: December 19, 2017
Previous studies reported that norcantharidin (NCTD) has anti-tumor effects. We investigated the antitumor effects and underlying mechanism of NCTD on human renal cancer in vitro and in vivo. NCTD significantly decreased renal cancer cell viability by induction of apoptosis, as determined by the MTT assay and annexin V/PI staining. NCTD treatment of 786-O and A-498 cells altered the expression of caspase family proteins and PARP. Moreover, NCTD induced mitochondrial depolarization, which was accompanied by an increased level of Bax and decreased levels of Bcl-2 and Mcl-1. NCTD induced endoplasmic reticulum (ER) stress by increasing the expression of Grp78, p-elF2α, ATF4, and CHOP. Pretreatment with an ER stress inhibitor (salubrinal) significantly attenuated the effect of NCTD. NCTD also induced activation of the AKT pathway in 786-O and A-498 cells. Overexpression of AKT partly reversed the effect of NCTD on apoptosis. NCTD treatment led to decreased expression of Bcl-2 and Mcl-1, and increased expression of Bax, cleaved-caspase-9, cleaved-PARP, and p-elF2α. Our in vivo studies demonstrated that NCTD significantly inhibited tumor growth in a nude mouse xenograft model. Taken together, our results suggest that NCTD is a potential anti-tumor agent for treatment of renal carcinoma.
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