Vitamin C exerts a concentration-dependent dual effect on melanoma progression through the ERK-PTPN12-JAK2 axis

The role of vitamin C (Vc) in cancer therapy has been debated for decades. Notably, Vc has a concentration-dependent dual effect on malignant melanoma; however, the underlying molecular mechanism remains to be explored. In this study, we aim to investigate the mechanism underlying these opposing effects. The effects of Vc on melanoma cell proliferation, cell migration, and apoptosis are assessed by the CCK-8 assay, wound healing assay, Transwell assay, and flow cytometry. The effect of Vc on tumor growth in vivo is determined using an xenograft mouse model. Molecular and biochemical methods are used to elucidate the mechanisms by which Vc modulates melanoma progression. We find that low-dose Vc promotes melanoma cell chemotactic migration and xenograft tumor growth, whereas high-dose Vc inhibits cell proliferation and migration, induces apoptosis, and suppresses tumor growth. Mechanistically, we identify a novel axis involving extracellular signal-regulated kinase (ERK), protein tyrosine phosphatase nonreceptor type 12 (PTPN12), and Janus kinase 2 (JAK2). Specifically, low-dose Vc-induced ERK activation increases PTPN12 phosphorylation at Ser⁴³⁴, which inhibits PTPN12-mediated dephosphorylation of JAK2, thereby increasing JAK2 activity. In contrast, high-dose Vc exerts the opposite effect by suppressing this axis. Furthermore, Vc regulates melanoma cell migration in a PTPN12-dependent manner. Our findings elucidate a novel mechanism involving the ERK-PTPN12-JAK2 axis in the influence of Vc on melanoma progression, underscore the therapeutic potential of high-dose Vc as a promising adjunctive therapy, and highlight the potential risk of low-dose supplementation.