Abstract LB-245: 9cis-retinoid UAB30 by inhibiting aberrant fatty acid metabolism protects against UVB-induced skin inflammation and carcinogenesis
Authors: Kashyap Mahendra P. , Waseem Mohammad , Li Changzhao , Iqbal Mohd Shameel , Atigadda Venkatram R. , Elmets Craig A. , Athar Mohammad 
Published: August 2019

Tumor cells are characterized by aberrant energy metabolism such as an accelerated glycolytic flux and enhanced de novo fatty acid (FA) synthesis which underlie the pathogenesis of aggressive cancer growth. Increased FA synthesis that commensurates with high metabolic demand of cancer cells could be targeted for the prevention or therapeutic intervention of cancer pathogenesis. Retinoids, are well known to inhibit cell proliferation and induce cellular differentiation/apoptosis in various tumor cell types. However, their use is often limited due to severe adverse effects including hyperlipidemia. We have developed 9cUAB30, a selective retinoid X receptors (RXR) agonist with potential anti-carcinogenic effects. Interestingly, it does not manifest hyperlipidemia both in experimental animals and in humans. Here, we demonstrate that chronic administration of 9cUAB30 to Ptch+/-/SKH1 mice diminishes expression of enzymes involved in de novo fatty acid synthesis as well as in UVB-induced inflammatory response. The metabolic analysis of tumor adjacent skin revealed that 9cUAB30 decreases levels of cutaneous saturated fatty acids as well as medium and long chain acetyl carnitines. Additionally, 9cUAB30 inhibits de novo lipid synthesis by inhibiting transcription factor, sterol regulatory element-binding protein 1 (SREBP-1). UVB-induced cutaneous inflammatory response was characterized by an increase in skin bi-fold thickness and edema as well as by augmented levels of pro-inflammatory cytokines/chemokines. 9cUAB30 administered soon after UVB irradiation, significantly diminished these inflammatory responses. Our data confirm that 9cUAB30 decreased the SREBP1-mediated transcription regulation of inflammasome components and its downstream pro-inflammatory cytokines/chemokines such as IL-1β and IL18. 9cUAB30 mediated alterations of UVB-induced pro-inflammatory signaling were identical to those mediated by fatostatin, a potent inhibitor of SREBP1 activation and these data further confirm the role of SREBP1 in UVB-induced inflammation. The molecular mechanism associated with anti-inflammatory response of 9cUAB30 was confirmed in skin tumor cells which are known to secrete pro-inflammatory cytokines to develop a tumor growth condusive micro-environment. Treatment of human squamous cell carcinoma A431 and SCC13 cells with 9cUAB30 (10, 20 and 30 μM) resulted in the downregulation of multiple proteins involved in de novo FA synthesis. The expression of Acetyl-CoA carboxylase 1 (ACC1), ATP citrate lyase (ACLY) and fatty acid synthase (FASN) was significantly reduced in these SCC cells, but not in normal keratinocyte (KerCT). 9cUAB30 reduced the expression of Sirt1 and Sirt2, deacetylases required for the activation of acetyl-CoA synthetase (AceCS1) and Acetyl-CoA production. The expression of CPT1B and CPT2, but not CPT1A (a critical enzyme required for FA β-oxidation) were also decreased. Additionally, 9cUAB30 was instrumental in decreasing the levels of ACADL, ACADM, HADHA and Sirtulin-3. These changes in FA driven energy metabolism underlie the reduced pathogenesis of xenograft tumors in nude mice. In summary, these data demonstrate a novel mechanism by which 9cUAB30 targets lipid metabolism-driven pro-inflammatory and pro-cancer signaling pathways to block the pathogenesis of skin cancer.

Citation Format: Mahendra P. Kashyap, Mohammad Waseem, Changzhao Li, Mohd Shameel Iqbal, Venkatram R. Atigadda, Craig A. Elmets, Mohammad Athar. 9cis-retinoid UAB30 by inhibiting aberrant fatty acid metabolism protects against UVB-induced skin inflammation and carcinogenesis [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 LB-245.