The Dietary Supplement Chondroitin-4-Sulfate Exhibits Oncogene-Specific Pro-tumor Effects on BRAF V600E Melanoma Cells

• Type of Material: Article
• Authors: Ruiting Lin, Emory University; Siyuan Xia, Emory University; Changliang Shan, Jinan University; Dong Chen, Emory University; Yijie Liu, Emory University; Xue Gao, Emory University; Mei Wang, Emory University; Hee-Bum Kang, Emory University; Yaozhu Pan, Emory University; Shuangping Liu, Emory University; Young Rock Chung, Memorial Sloan-Kettering Cancer Center; Omar Abdel-Wahab, Memorial Sloan-Kettering Cancer Center; Taha Merghoub, Memorial Sloan-Kettering Cancer Center; Michael Rossi, Emory University; Ragini Kudchadkar, Emory University; David Lawson, Emory University; Fadlo Khuri, Emory University; Sagar Lonial, Emory University; Jing Chen, Emory University
• Language: English
• Date: 2018-03-15
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2018.02.010
• Title of Journal or Parent Work: Molecular Cell
• ISSN: 1097-2765
• Volume: 69
• Issue: 6
• Start Page: 923
• End Page: +
• Grant/Funding Information: This work was supported in part by NIH grants CA140515, CA183594, CA174786 (J.C.), Joel A. Katz Music Medicine Fund supported by the T.J. Martell Foundation/Winship Cancer Institute (J.C. and R.L.).; R.L. is a Special Fellow of The Leukemia & Lymphoma Society.; J.C. is a Winship 5K Scholar.
• Keywords: GROWTH; RISK; SULFATE; GLUCOSAMINE; Cell Biology; PROSTATE-CANCER; KNEE OSTEOARTHRITIS; PATHWAY; DISEASE PREVENTION; Life Sciences & Biomedicine; Science & Technology; PROTEIN-KINASE-B; UNITED-STATES; Biochemistry & Molecular Biology
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology; Health Sciences, Pathology

Abstract

Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors. Mechanistically, chondroitin sulfate glucuronyltransferase (CSGlcA-T) signals through its product CHSA to enhance casein kinase 2 (CK2)-PTEN binding and consequent phosphorylation and inhibition of PTEN, which requires CHSA chains and is essential to sustain AKT activation in BRAF V600E-expressing melanoma cells. However, this CHSA-dependent PTEN inhibition is dispensable in cancer cells expressing mutant NRAS or PI3KCA, which directly activate the PI3K-AKT pathway. These results suggest that dietary supplements may exhibit oncogene-dependent pro-tumor effects. The pathogenic links between dietary supplements and oncogenic mutations remain unknown. In this article, Lin et al. demonstrate that chondroitin-4-sulfate, a dietary supplement widely used for osteoarthritis, selectively promotes BRAF-V600E melanoma growth and confers resistance to BRAF inhibitors, suggesting that the generally “safe” dietary supplements may exhibit oncogene-specific pro-tumor effects.