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- Title
Switching mechanism from AR to EGFR signaling via 3-O-sulfated heparan sulfate in castration-resistant prostate cancer.
- Authors
Ota, Hayato; Sato, Hirokazu; Mizumoto, Shuji; Wakai, Ken; Yoneda, Kei; Yamamoto, Kazuo; Nakanishi, Hayao; Ikeda, Jun-Ichiro; Sakamoto, Shinichi; Ichikawa, Tomohiko; Yamada, Shuhei; Takahashi, Satoru; Ikehara, Yuzuru; Nishihara, Shoko
- Abstract
Androgen deprivation therapy is given to suppress prostate cancer growth; however, some cells continue to grow hormone-independently as castration-resistant prostate cancer (CRPC). Sulfated glycosaminoglycans promote ligand binding to receptors as co-receptors, but their role in CRPC remains unknown. Using the human prostate cancer cell line C4-2, which can proliferate in hormone-dependent and hormone-independent conditions, we found that epidermal growth factor (EGF)-activated EGFR–ERK1/2 signaling via 3-O-sulfated heparan sulfate (HS) produced by HS 3-O-sulfotransferase 1 (HS3ST1) is activated in C4-2 cells under hormone depletion. Knockdown of HS3ST1 in C4-2 cells suppressed hormone-independent growth, and inhibited both EGF binding to the cell surface and activation of EGFR–ERK1/2 signaling. Gefitinib, an EGFR inhibitor, significantly suppressed C4-2 cell proliferation and growth of a xenografted C4-2 tumor in castrated mouse. Collectively, our study has revealed a mechanism by which cancer cells switch to hormone-independent growth and identified the key regulator as 3-O-sulfated HS.
- Subjects
CASTRATION-resistant prostate cancer; HEPARAN sulfate; ANDROGEN receptors; EPIDERMAL growth factor receptors; EPIDERMAL growth factor; ANDROGEN deprivation therapy
- Publication
Scientific Reports, 2023, Vol 13, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-023-38746-x