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

Abstract

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.

• Authors: 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 298 Issue 3 Pg. 101594 (03 2022) ISSN: 1083-351X [Electronic] United States
• PMID: 35041825 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, CD
• Sialyltransferases
• ST6GAL1 protein, human
• N-Acetylneuraminic Acid
• beta-D-Galactoside alpha 2-6-Sialyltransferase

Topics

• Antigens, CD (metabolism)
• Apoptosis (drug effects, radiation effects)
• Chemoradiotherapy
• Drug Resistance, Neoplasm
• Humans
• N-Acetylneuraminic Acid (metabolism)
• Radiation Tolerance
• Rectal Neoplasms (drug therapy, metabolism, pathology, radiotherapy)
• Sialyltransferases (genetics, metabolism)
• beta-D-Galactoside alpha 2-6-Sialyltransferase