RPS3 regulates melanoma cell growth and apoptosis by targeting Cyto C/Ca2+/MICU1 dependent mitochondrial signaling

// Yun Tian 1, * , Lijun Qin 3, * , Huijuan Qiu 1, * , Dingbo Shi 1 , Rui Sun 1 , Wenbing Li 1 , Tianze Liu 1 , Jingshu Wang 1 , Tingting Xu 4 , Wei Guo 4 , Tiebang Kang 1 , Wenlin Huang 1, 5 , Guowen Wang 2, * , Wuguo Deng 1, 5, * 1 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China 2 Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China 3 Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou China 4 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China 5 State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China * These authors have contributed equally to this work Correspondence to: Guowen Wang, e-mail: wangguowendr@163.com Wuguo Deng, e-mail: dengwg@sysucc.org.cn Keywords: melanoma, RPS3, MICU1, calcium ion, mitochondrial Received: March 27, 2015      Accepted: August 12, 2015      Published: August 22, 2015 ABSTRACT Melanoma is one of the most aggressive and lethal cancers. Discovery and identification of novel therapeutic targets is urgently needed. In this study, we demonstrated that ribosomal protein S3 (RPS3) was a potential target involved in melanoma growth. Knockdown of RPS3 by siRNA suppressed cell growth and induced apoptosis in melanoma cells. Further mechanism studies showed that RPS3 knockdown in melanoma cells triggered the release of cytochrome C (Cyto C) from mitochondrial, increased the location of BID on mitochondrial membrane and the cleavage of the pro-apoptotic proteins (PARP, caspase-3 and -9), promoted the opening of mitochondrial permeability transition pore and the flooding of calcium ions (Ca 2+ ) into the mitochondrial, and decreased the expression of the Ca 2+ gatekeeper MICU1 and its location on the mitochondrial. We also found that knockdown of RPS3 significantly inhibited tumor growth in a melanoma xenograft mouse model. Furthermore, we showed that RPS3 was highly expressed in melanoma cell lines and melanoma tumor tissues, and overexpression of RPS3 was associated with the poor prognosis of melanoma patients. Our results therefore demonstrate that RPS3 regulates melanoma growth through the modulation of the Cyto C/Ca2+/MICU1 dependent mitochondrial signaling and suggest that RPS3 is a potential therapeutic target for melanoma treatment.