Abstract P2-16-02: TXNIP-dependent tumor suppressive pathways in breast cancer growth and progression

Abstract

Abstract Thioredoxin-interacting protein (TXNIP) plays a critical role in glucose metabolism and redox signaling through negatively regulating thioredoxin activity. Over the past decade, TXNIP has emerged as a novel tumor suppressor in various cancer models. In search of the molecular targets mediating the anticancer effect of an epigenetic drug UNC0642, we found TXNIP to be consistently upregulated by UNC0642, which was coupled with significant suppression of MDA-MB-231 breast cancer cell proliferation in vitro and tumor growth in vivo. TXNIP knockdown increased MDA-MB-231 cell proliferation and in vivo tumor growth and metastasis. In contrast, TXNIP-reconstitution in TXNIP-deficient HCC1954 breast cancer cells suppressed cell proliferation and migration that is coupled with increases in reactive oxygen species, strongly supporting TXNIP’s potent antitumor function. TXNIP-reconstitution also decreased mitochondrial respiration and glycolysis in HCC-1954 cells as determined by using the Agilent Seahorse XF Cell Energy assays. To understand the molecular targets through which TXNIP exerted its antitumor activity, we performed co-immunoprecipitation studies and proteomic analyses to identify TXNIP-interacting proteins in UNC0642-treated MDA-MB-231 cells. Besides thioredoxin, we identified peroxiredoxin-6 (PRDX6), another modulator of cellular redox signaling, as a major TXNIP-interacting protein. While Prdx6-knockout mice develop normally, PRDX6 is frequently upregulated in breast cancer patients that is significantly associated with aggressive tumor subtypes and poor overall survival. The mechanism underlying the role of PRDX6 in breast oncogenesis remains elusive. Our findings suggest that TXNIP might exert its antitumor activity through binding and inhibiting PRDX6 activity in breast cancer cells to alter ROS signaling, thus providing novel therapeutic targets and potential prognostic biomarkers for breast cancer patients. Citation Format: Jasvinder Singh, Bindeshwar sah, Liang Liu. TXNIP-dependent tumor suppressive pathways in breast cancer growth and progression [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-02.