Abstract
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.
Highlights
Renal cell carcinoma (RCC) is the ten most frequently occurring human cancers [1]
We initially investigated the effect of NCTD on the viability of four human renal cancer cells (786-O, A-498, CaKi-1, and ACHN) and normal proximal tubule epithelial cells (HK-2) using the MTT assay
Our results indicate that NCTD suppresses the growth of human renal cancer cells in vitro and in vivo by induction of cell cycle arrest www.impactjournals.com/oncotarget and apoptosis, and this is due to its effect on endoplasmic reticulum (ER) stress and the AKT signaling pathway
Summary
Renal cell carcinoma (RCC) is the ten most frequently occurring human cancers [1]. RCC develops from the proximal renal tubular epithelial cells of the kidneys, and accounts for about 85% of renal cancers [2]. It is necessary to better understand the molecular mechanisms of this cancer so that new anti-RCC molecular targets can be identified and effective and less toxic drugs can be developed. NCTD has diverse anticancer activities against various types of tumor cells, such as prostate cancer, lung cancer, breast cancer, and colorectal carcinoma [10,11,12,13]. Other studies reported that NCTD induces mitochondria-dependent apoptosis through inhibition of the AKT/FOXO4/Mcl signaling pathway in human prostate cancer [15] and induces production of reactive oxygen species (ROS) via upregulation of the p38 MAPK pathway in human urinary bladder carcinoma cells [16]. The underlying molecular mechanisms of the anti-tumor effects of NCTD on renal cancer cells are still unknown
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