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

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.

Expression and function of chondroitin 4‐sulfate and chondroitin 6‐sulfate in human glioma

“…Inactivation of this pathway reduced C4S‐ and C6S‐induced EMT conversion and MMP‐2 levels, resulting in the reduction of cell migration and invasion. These results are in agreement with the finding that C4S dose‐dependently increases p‐AKT levels in A375 melanoma cells . CSs also increased p‐AKT levels in SH‐SY5Y neuroblastoma cells under oxidative stress, without indication of the type of CSs used in this study .…”

“…These results are in agreement with the finding that C4S dose-dependently increases p-AKT levels in A375 melanoma cells. 31 CSs also increased p-AKT levels in SH-SY5Y neuroblastoma cells under oxidative stress, without indication of the type of CSs used in this study. 51 Combined with previous observations, our results show that individual CSs induce glioma cell EMT conversion and increase MMP expression by activating the PI3K/AKT signaling pathway in parallel with enhanced cell migration and invasion.…”

“…The addition of C4S to cultured melanoma cells promotes their proliferation through the PTEN/PI3K/AKT pathway and enhances resistance to b-Raf proto-oncogene inhibitors. 31 It has also been reported that CSs promote the proliferation of breast cancer cells and the growth of Ehrlich ascites tumors in vivo, suggesting that increased CS levels increase the interaction with positively charged growth factors, thereby enhancing tumor cell proliferation and growth. [32][33][34] CSs have been shown to promote U-87 MG cell invasion by upregulating the expression of the chemokine receptor CXCR4 and CSPG receptor LAR.…”

Thu0449 effect Moderation of Analgesic Treatment Outcomes by Depression in Persons With or at-Risk for Symptomatic Knee Osteoarthritis

“…Thus, knee OA patients with depression may derive more benefit from analgesic treatment for chronic pain than non-depressed patients, perhaps because their pain is undertreated in routine clinical practice. (2018), sarcopenia is a muscle disease (muscle failure) rooted in adverse muscle changes that accrue across a lifetime [1]. Sarcopenia and osteoarthritis significantly affect the self-esteem quality of life which is associated with a decrease in muscle strength and muscle performance, falls, joint pain [2].…”

“…Background: Chondroitin sulfate (CS) is widely used nutritional supplement for the treatment of osteoarthritis. There is growing in vitro evidence that CS may play a role in oncogenesis and metastasis of several solid tumors including melanoma [1] and breast cancer [2]. The data evaluating pro-oncogenic effects of CS in humans are lacking.…”