Abstract 4806: SIRT5 inhibition causes increased oxidative stress and impairs tumor progression and metastasis

Cancer cells undergo metabolic reprogramming, producing energy through aerobic glycolysis followed by lactic acid fermentation. Consequently, targeting key metabolic enzymes has emerged as a potential avenue to selectively inhibit tumor growth. The sirtuin family of deacylases has roles in both metabolism and cancer. The mitochondrial sirtuin SIRT5 regulates protein post-translational modifications on metabolic enzymes by catalyzing the removal of succinyl, malonyl, and glutaryl moieties. SIRT5 is over-expressed in many cancers, including breast cancer. Therefore, we hypothesized that SIRT5 promotes breast cancer progression by facilitating metabolic reprogramming. SIRT5 knockdown in human cancer cells inhibited anchorage independent growth but had little effect on non-transformed cells. To examine how SIRT5 loss impacts tumorigenesis in vivo, we utilized MMTV-PyMT transgenic mice, which are prone to mammary adenocarcinoma and lung metastasis. SIRT5 knockout (KO) MMTV-PyMT mice had increased survival, decreased tumor size, and reduced lung metastases, as compared to SIRT5 wild-type (WT) MMTV-PyMT controls. SIRT5 KO cancer cells had higher levels of reactive oxygen species and displayed lower levels of important antioxidants such as NADPH and GSH. These results suggest that SIRT5 KO cells are more susceptible to oxidative stress, hinting that SIRT5 may be promoting breast cancer by mitigating ROS through one or more of its key metabolic substrates. To determine the therapeutic potential of SIRT5 inhibition, we created potent and specific small molecule SIRT5 inhibitors. Pharmacological inhibition of SIRT5 impaired mammary tumor growth in both transgenic and human breast cancer xenograft mouse models, with no apparent toxicity. Considering that Sirt5 knockout mice are generally normal, with only mild phenotypes observed, these data establish SIRT5 as a promising target for treating breast cancer. Citation Format: Irma Fernandez, Yashira N. Abril, Jun Y. Hong, Min Yang, Sushabhan Sadhukhan, Hening Lin, Robert Weiss. SIRT5 inhibition causes increased oxidative stress and impairs tumor progression and metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4806.