An altered profile of surface glycans is a well-known feature of tumor cells; however the molecular mechanisms by which specific glycans and associated glycosyltransferases regulate tumor cell behavior remain elusive. Work from our group has determined that the ST6Gal-I sialyltransferase endows ovarian cancer (OC) cells with the ability to avoid apoptosis induced by multiple stimuli including galectins, death receptor activators and chemotherapeutic drugs. In this proposal we show for the first time that ST6Gal-I protein is upregulated in the great majority of human ovarian tumors, including the lethal papillary serous adenocarcinoma subtype. Upregulation of ST6Gal-I correspondingly causes hypersialylation of selected receptors including the 1 integrin, Fas and TNFR1. In paradigm-shifting mechanistic studies, we find that ST6Gal-I-mediated sialylation of Fas and TNFR1 prevents receptor internalization, causing a shift in the signaling of these receptors toward survival rather than apoptosis. Additionally, ST6Gal-I activity confers resistance to apoptotic galectin-3 and the chemotherapeutic, cisplatin. The central hypothesis of this proposal is that ST6Gal-I overexpression underlies two crucial factors contributing to OC lethality: tumor cell resistance to platinum-based chemotherapy (Aim 1), and OC cell protection against immune stimuli within the peritoneal tumor microenvironment (Aim 2), which is rich in gal-3 as well as ligands for Fas and TNFR1. Preliminary studies show that ST6Gal-I promotes OC cell survival within patient peritoneal ascites fluid; this finding is significant in that OC cells metastasize va peritoneal transit.
AIM 1 : ST6Gal-I-mediated receptor sialylation in chemoresistance. We will define molecular mechanisms responsible for ST6Gal-I's role in cisplatin resistance, and determine whether receptor sialylation controls chemoresistance within the intact tumor microenvironment. Efficacy of cisplatin treatment will be evaluated for orthotopic tumors established in mice from OC cells with differential ST6Gal-I expression, and in vivo delivery of RNAi will be used to implement therapeutic knockdown of ST6Gal-I to restore cisplatin sensitivity. ST6Gal-I will be quantified in chemosensitive vs. chemoresistant human tumors to assess its prognostic potential.
AIM 2 : Contribution of ST6Gal-I to tumor cell survival within the peritoneal microenvironment Mechanisms underlying ST6Gal-I-dependent OC cell survival within ascites will be elucidated, with a focus on gal-3/ 1 integrin, FasL/Fas, and TNF?/TNFR1 interactions. ST6Gal-I-mediated protection of OC cells from cytotoxic immune cells will be examined, and human ovarian tumors screened for an association between ST6Gal-I and immune cell infiltration. The growth of orthotopic tumors +/- ST6Gal-I will be monitored in immunocompetent mice. The studies will have impact by showing that ST6Gal-I is a master regulatory molecule controlling tumor/ microenvironmental interactions that regulate the balance between elimination vs. persistence of OC cells that drive tumor recurrence. Innovation lies in the elucidation of: (1) novel glycosylation-dependent tumor mechanisms, and (2) a new molecular player in OC pathogenesis and biomarker for patient chemoresistance.

Public Health Relevance

Decades of research have yielded only minor gains in the survival of patients with ovarian cancer, highlighting the need for alternative approaches. The proposed research will focus on the role of a unique glycosyltransferase, ST6Gal-I, in conferring resistance of ovarian cancer cells to cell death pathways induced by chemotherapeutic drugs and immune mediators. Therapeutic targeting of this enzyme is expected to open new avenues for preventing OC tumor recurrence, enhancing immunotherapy, and restoring tumor cell sensitivity to clinical chemotherapy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Marino, Pamela
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University of Alabama Birmingham
Anatomy/Cell Biology
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United States
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Chakraborty, Asmi; Dorsett, Kaitlyn A; Trummell, Hoa Q et al. (2018) ST6Gal-I sialyltransferase promotes chemoresistance in pancreatic ductal adenocarcinoma by abrogating gemcitabine-mediated DNA damage. J Biol Chem 293:984-994
Shin, Boyoung; Kress, Robert L; Kramer, Philip A et al. (2018) Effector CD4 T cells with progenitor potential mediate chronic intestinal inflammation. J Exp Med 215:1803-1812
Holdbrooks, Andrew T; Britain, Colleen M; Bellis, Susan L (2018) ST6Gal-I sialyltransferase promotes tumor necrosis factor (TNF)-mediated cancer cell survival via sialylation of the TNF receptor 1 (TNFR1) death receptor. J Biol Chem 293:1610-1622
Britain, Colleen M; Holdbrooks, Andrew T; Anderson, Joshua C et al. (2018) Sialylation of EGFR by the ST6Gal-I sialyltransferase promotes EGFR activation and resistance to gefitinib-mediated cell death. J Ovarian Res 11:12
Jones, Robert B; Dorsett, Kaitlyn A; Hjelmeland, Anita B et al. (2018) The ST6Gal-I sialyltransferase protects tumor cells against hypoxia by enhancing HIF-1? signaling. J Biol Chem 293:5659-5667
Britain, Colleen M; Dorsett, Kaitlyn A; Bellis, Susan L (2017) The Glycosyltransferase ST6Gal-I Protects Tumor Cells against Serum Growth Factor Withdrawal by Enhancing Survival Signaling and Proliferative Potential. J Biol Chem 292:4663-4673
Schultz, Matthew J; Holdbrooks, Andrew T; Chakraborty, Asmi et al. (2016) The Tumor-Associated Glycosyltransferase ST6Gal-I Regulates Stem Cell Transcription Factors and Confers a Cancer Stem Cell Phenotype. Cancer Res 76:3978-88