Abstract 3085: A novel salicylanilide derivative inhibits castration-resistant prostate cancer via endoplasmic reticulum stress-triggered PERK autophagic signaling pathway

Abstract

Abstract Background and Purpose: Metastatic castration-resistant prostate cancer (CRPC) is currently incurable. This study is to extend pharmacological value of our synthesized salicylanilide derivative, that has previously testified for its osteoclastogenesis activity, by exploring its additional cytotoxic properties and underlying mechanism in CRPC cells. Experimental Approach: LCC03, a 5-(2′,4′-Difluorophenyl)-salicylanilide derivatives, was chemically synthesized and examined for cell growth inhibition in a serial of CRPC cell lines. Possible mechanisms involved in the anticancer activity was elucidated based on the changes in pathway-related protein expression and cellular events, together with antagonists for functional validation. The therapeutic efficacy and safety of LCC03 for the treatment of bone metastatic CRPC was evaluated in an experimental animal model. Key Results: LCC03 dose-dependently suppressed proliferation and retarded cell cycle progression in CRPC cells. The classical autophagy features including autophagsomes formation and LC3-II conversation were dramatically shown in LCC03-treated CRPC cells, and it was associated with the suppressed AKT/mTOR signaling pathways, a major negative regulator of autophagy, Moreover, an expanded morphology of the ER, increased expression of the ER stress markers GRP78 and PERK, and eIF2α phosphorylation were observed. Blockage of autophagy and PERK pathways using small molecule inhibitors or shRNA knockdown reversed LCC03-induced autophagy and cell death, thus indicating that the PERK-eIF2α pathway contributed to the autophagy induced by LCC03. Furthermore, treatment of tumor-bearing mice with intraperitoneal administered LCC03 suppressed the growth of CRPC xenografts in mouse bone without systemic toxicity. Conclusion and Implications: LCC03 induces cellular responses toward ER stress-induced autophagy via the PERK-eIF2α pathway that impairs proliferation and cell cycle progression and exhibits cytotoxicity against CRPC cells. The dual action of 5-(2′,4′-difluorophenyl)-salicylanilide on both the osteoclasts and the tumor cells strongly indicates that LCC03 is a promising anticancer candidate for preventing and treating metastatic CRPC. Citation Format: Chia-Ling HSIEH, Hsu-Shan Hung, Kuan-Chou Chen, Teigi Saka, Chih-Ying Chiang, Shian-Ying Sung. A novel salicylanilide derivative inhibits castration-resistant prostate cancer via endoplasmic reticulum stress-triggered PERK autophagic signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3085.