Abstract 5345: Novel approach to attenuate melanoma initiation and progression

Abstract

Abstract Background and Purpose: Melanocytic nevi are benign proliferations of melanocytic cells that are positively correlated with susceptibility to melanoma. Polyaromatic hydrocarbons (PAH) are ubiquitous environmental pollutants that are potent mutagens and carcinogens, and the investigators have taken advantage of these properties to investigate the mechanisms by which chemicals cause cancer of the skin and other organs. In comparison to C57Bl/6 strain, C3H/HeN mice are more susceptible to the development of PAH induced tumors. Therefore, a mouse model of nevus initiation and progression was developed in C3H/HeN mice using a modified chemical carcinogenesis protocol. Experimental Design: In the traditional two-stage skin carcinogenesis model, initiation is accomplished by the application of a subcarcinogenic dose of a carcinogen. Subsequently, tumor development is elicited by repeated treatment with a tumor promoting agent. Nevi develop due to DNA damage initiated by 7, 12-dimethylbenz[a]anthracene (DMBA) followed by chronic promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Results: Dysplastic pigmented skin lesions appeared in ~10 wk with 100% penetrance. Studies reported here demonstrating that inhibition or depletion of RLIP results in apoptosis and cancer regression in an exceptionally broad spectrum on neoplasia have suggested an intriguing possibility that RLIP is an anti-apoptotic mechanism required not only for the survival of cancer cells, but also for their very existence. In support of this assertion results presented here that the well-known carcinogens, DMBA and phorbol esters (PMA or TPA) are ineffective in causing neoplasia in C3H/HeN mice treated with RLIP-targeting agent’s (RLIP antibodies and RLIP antisense). Here we demonstrate that DMBA/PMA-induced skin carcinogenesis in C3H/HeN mouse was suppressed completely by depletion of RLIP by antisense or inhibition by antibodies. In addition, C3H/HeN mice treated with RLIP-targeting agent’s, p53, P38, and JNK activation did not occur in response to carcinogens. These findings demonstrate a fundamental role of RLIP in chemical carcinogenesis. Conclusions: We demonstrate that RLIP expression is significantly greater in cancer cells than in non-malignant cells, and RLIP-targeting agent’s (RLIP antibodies and RLIP antisense) treatment was significantly suppress the generation of melanocytic nevi and their progression to melanoma. (This work was supported in part by the Department of Defense grants W81XWH-16-1-0641 and W81XWH-20-1-0362. Funding from the Beckman Research Institute of City of Hope is also acknowledged). Citation Format: Sharad S. Singhal, Prakash Kulkarni, Jyotsana Singhal, David Horne, Sanjay Awasthi, Ravi Salgia. Novel approach to attenuate melanoma initiation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5345.