Abstract 295: Targeting spermine synthase triggers lipid metabolism reprogramming as a new therapeutic option to combat colorectal cancer

Abstract

Abstract Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC). Our recent work demonstrates that spermine synthase (SMS), a polyamine biosynthetic enzyme that converts spermidine to spermine, is overexpressed in CRC, which is required for balancing cellular spermidine levels to facilitate CRC tumorigenesis (Nat Commun 11:3243, 2020). Our findings reveal SMS as an attractive therapeutic target in CRC; yet, genetic depletion of SMS expression only shows a limited antitumor effect. Using unbiased metabolomics and transcriptomics analyses, we identified a lipid metabolism reprograming as among the most impacted metabolic change by SMS depletion in CRC cells. Specifically, SMS depletion significantly altered long-chain fatty acid, triacylglycerol and phospholipid metabolism. Furthermore, targeted inhibition of SMS significantly increased the number of lipid droplets and the levels of long-chain fatty acid acylcarnitines for oxidative phosphorylation in mitochondria, and upregulated expression of genes associated with increased mobilization of polyunsaturated fatty acids and the genes associated with lipid peroxidation for induction of ferroptosis, an iron-dependent form of nonapoptotic cell death. The glutathione peroxidase 4 (GPX4) is a key negative regulator of ferroptosis by neutralizing lipid peroxides. Notably, pharmacological inhibition of GPX4 or its upstream regulator system xc − in combination with genetic depletion or pharmacologic inhibition of SMS synergistically caused lipid peroxidation leading to ferroptosis induction and marked suppression of CRC cell growth. Collectively, these findings highlight lipid metabolism reprograming as an adaptive response to targeted inhibition of SMS to enable CRC cell survival, which represents an Achilles’ heel that can be exploited for potential effective therapy for CRC. Citation Format: Murong Ma, Yubin Guo, Qing Ye, Pan Deng, Daheng He, Chi Wang, Qing-Bai She. Targeting spermine synthase triggers lipid metabolism reprogramming as a new therapeutic option to combat colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 295.