Rps3 Regulates Melanoma Growth And Sensitivity To Dna Damage And Predicts A Poor Prognosis By Targeting Adt3

Melanoma, a malignant skin cancer, is resistant to DNA damage-mediated therapy. Discovering and identifying novel therapeutic targets for melanoma is urgently required. In this study, we found that ribosome protein S3 (RPS3) regulated melanoma growth and the sensitivity of melanoma to DNA damage by targeting ADP/ATP translocase 3 (ADT3). Knockdown of RPS3 inhibited cell proliferation and sensitized melanoma cells to DNA damage. RPS3 knockdown also promoted ADT3 translocation to mitochondrial of melanoma cells when exposed to DNA damage. RPS3 interacted with ADT3 in melanoma cells. Knockdown of ADT3 reduced its co-localization with RPS3. RPS3 could not obviously sensitize melanoma cells to DNA damage with ADT3 knockdown. In addition, we found that Lys18 in the death-induce-domain of RPS3 protein played a critical role in the interaction between RPS3 and ADT3. Mutation at Lys18 site could deadlock ADT3 and attenuate cell apoptosis in melanoma cells. Knockdown of RPS3 also inhibited tumor growth in a melanoma mouse model in vivo, but overexpression of the RPS3-18 mutation rescued the growth. Furthermore, we showed that the patients with higher expressed RPS3 had a much shorter median survival, whereas the patients with higher levels of ADT3 had a much longer median survival. Collectively, our results indicate that RPS3 cooperates with ADT3 to regulate the sensitivity of melanoma to DNA damage and suggest that the RPS3/ADT3 pathway is a potential therapeutic target for human melanoma. Grant support: This work was supported by the funds from the National Natural Science Foundation of China (81472178, 81272195) and the State “973 Program” of China (2014CB542005). Citation Format: Yun Tian, Lijun Qin, Wei Guo, Changlin Zhang, Dingbo Shi, Tianze Liu, Wenbing Li, Jingshu Wang, Yixin Li, Ge Qin, Wendan Yu, Xiangsheng Xiao, Tiebang Kang, Wenlin Huang, Wuguo Deng. RPS3 regulates melanoma growth and sensitivity to DNA damage and predicts a poor prognosis by targeting ADT3. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3597.