Abstract 2797: Role of the ST6Gal-I glycosyltransferase in protecting tumor cells against hypoxia

Abstract

Abstract A change in surface glycosylation was one of the first identified hallmarks of a cancer cell, however an understanding of how altered glycosylation affects cancer cell biology remains unclear. Our group has shown that ST6Gal-I, a glycosyltransferase that adds negatively charged sialic acids to surface receptors in a α2-6-linked manner, is upregulated in many cancer types. Through modulating the activity of various receptors, ST6Gal-I can act as a pro-survival factor in a variety of settings, including resistance to some chemotherapeutics. Tumor microenvironment plays a crucial role in cancer progression. One key component of the tumor microenvironment is the availability of oxygen, and in solid tumors there can be areas of hypoxia. Hypoxia leads to the induction of hypoxia inducible factors (HIFs), which are transcriptional regulators of the cellular response to low oxygen tension. HIFs such as HIF-1a, regulate the transcription of many proteins necessary for cells to survive when challenged by hypoxia. In this study we demonstrated that forced overexpression of ST6Gal-I in both ovarian and pancreatic cancer cell lines increased the stabilization of HIF-1a after treatment with the hypoxia mimetics desferrioxamine and DMOG, and when grown in a hypoxic environment. Correspondingly, knockdown of ST6Gal-I inhibited the stabilization of HIF-1a in these same conditions. Additionally, ST6Gal-I activity stimulates pro-survival signaling through phosphorylated NFκB and AMPK in these same models. These signaling pathways have been shown to be important for cellular survival in hypoxic environments. Markers of HIF-1a-induced transcription were investigated through qRT-PCR, and it was revealed that the ST6Gal-I-mediated stabilization of HIF-1a increased the levels of PDHK1and GLUT1 mRNA. Both GLUT1 and PDHK1 promote the shift in glucose metabolism when cells are in a low oxygen environment. Taken together, these data indicate that ST6Gal-I acts as a pro-survival factor by eliciting a more robust response by HIF-1a. The finding that a glycosyltransferase regulates the cellular response to hypoxia represents a novel paradigm in hypoxia signaling. Citation Format: Robert B. Jones. Role of the ST6Gal-I glycosyltransferase in protecting tumor cells against hypoxia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2797.