Sialyltransferase ST6GAL-1 mediates resistance to chemoradiation in rectal cancer.

Mary Smithson, Regina Irwin, Gregory Williams, Katie L Alexander, Lesley E Smythies, Marie Nearing, M Chandler McLeod, Sameer Al Diffalha, Susan L Bellis, Karin M Hardiman

The Journal of biological chemistry 2022 Mar

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Locally advanced rectal cancer is typically treated with chemoradiotherapy followed by surgery. Most patients do not display a complete response to chemoradiotherapy, but resistance mechanisms are poorly understood. ST6GAL-1 is a sialyltransferase that adds the negatively charged sugar, sialic acid (Sia), to cell surface proteins in the Golgi, altering their function. We therefore hypothesized that ST6GAL-1 could mediate resistance to chemoradiation in rectal cancer by inhibiting apoptosis. Patient-derived xenograft and organoid models of rectal cancer and rectal cancer cell lines were assessed for ST6GAL-1 protein with and without chemoradiation treatment. ST6GAL-1 mRNA was assessed in untreated human rectal adenocarcinoma by PCR assays. Samples were further assessed by Western blotting, Caspase-Glo apoptosis assays, and colony formation assays. The presence of functional ST6GAL-1 was assessed via flow cytometry using the Sambucus nigra lectin, which specifically binds cell surface α2,6-linked Sia, and via lectin precipitation. In patient-derived xenograft models of rectal cancer, we found that ST6GAL-1 protein was increased after chemoradiation in a subset of samples. Rectal cancer cell lines demonstrated increased ST6GAL-1 protein and cell surface Sia after chemoradiation. ST6GAL-1 was also increased in rectal cancer organoids after treatment. ST6GAL-1 knockdown in rectal cancer cell lines resulted in increased apoptosis and decreased survival after treatment. We concluded that ST6GAL-1 promotes resistance to chemoradiotherapy by inhibiting apoptosis in rectal cancer cell lines. More research will be needed to further elucidate the importance and mechanism of ST6GAL-1-mediated resistance. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Mary Smithson, Regina Irwin, Gregory Williams, Katie L Alexander, Lesley E Smythies, Marie Nearing, M Chandler McLeod, Sameer Al Diffalha, Susan L Bellis, Karin M Hardiman. Sialyltransferase ST6GAL-1 mediates resistance to chemoradiation in rectal cancer. The Journal of biological chemistry. 2022 Mar;298(3):101594