Abstract 4324: IL6ST increases sorafenib-resistance in hepatocellular carcinoma by regulating BECN1-mediated mitophagic cell death

Abstract

Abstract Introduction: Sorafenib resistance is often seen in patients with late-stage hepatocellular carcinoma (HCC) and it is a serious concern for the treatment of these patients. Lethal mitophagy plays an important role in anti-tumorigenic mechanisms by inducing mitochondrial dysfunction and mitophagic cell death. Sorafenib resistance is associated with the activation of IL6ST signaling, inhibiting mitochondrial quality. However, how lethal mitophagy regulates sorafenib resistance through IL6ST and mitochondrial dysfunction in HCC is not fully understood. Experimental procedures: Hepatocyte-specific TAK1 deleted (TAK1ΔHep) and TAK1/IL6STΔHep were used for in vivo study. Histology, immunoblots, qPCR, microscopy, FACS, and seahorse bioanalyzer were used for analyzing liver and tumor tissues and Hep3B cells. Results: We identified that sorafenib suppressed IL6ST signaling and that IL6ST signaling was activated in sorafenib-resistant HCC. The number and maximum size of spontaneous HCC in 9-month-old TAK1ΔHep mice were decreased when hepatocyte IL6ST was additionally deleted. Expression of pro-carcinogenic H-19, c-SRC, and MDM2 was increased in 1-month-old TAK1/IL6STΔHep mice compared to TAK1ΔHep mice. An additional IL6ST deletion induced decreases in mitochondrial membrane potential and glycolysis, suggesting that IL6ST protects against mitochondrial dysfunction. Interestingly, IL6ST deletion increases PRKN and BECN1 interaction and translocation to normal mitochondria and subsequent degradation, hereafter referred to as lethal mitophagy. Furthermore, inhibition of BECN1 restores IL6ST deletion-induced lethal mitophagy in HCC, suggesting that IL6ST-mediated lethal mitophagy is dependent on BECN1. Mechanistically, IL6ST inhibited BECN1-lethal mitophagy through STAT3(S705) phosphorylation independently of mTORC1 activation. Notably, enhanced BECN1 through a combination of sorafenib and inhibition of IL6ST increased mitophagic cell death, reducing sorafenib resistance and tumor growth. In addition, enhanced lethal mitophagy through inhibition of GP130 effectively killed sorafenib-resistant HCCs by silencing sorafenib resistance. We further defined the relationship between IL6ST, BECN1, and PRKN expression and sorafenib resistance in terms of HCC patients, RNA sequencing datasets. Conclusion: These results provide the importance of IL6ST in the development of sorafenib resistance and could be an innovative treatment strategy for sorafenib-resistant patients by regulating the IL6ST/STAT3/BECN1 axis-regulated lethal mitophagy. Citation Format: Hwan Ma, Yoon-Seok Roh. IL6ST increases sorafenib-resistance in hepatocellular carcinoma by regulating BECN1-mediated mitophagic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4324.