The tumor promoter 12-O-tetradecanoylphorbol-13-acetate suppresses cell proliferation in metastatic melanoma through TC-PTP/PTPN2 and SH-PTP2/PTPN11.

Despite being a carcinogen, the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits metastatic melanoma growth by downregulating signal transducer and activator of transcription 3 (STAT3). However, the molecular mechanisms remain unclear. The aim of this study was to identify tyrosine phosphatases that are involved in TPA-induced inhibition of cell proliferation in metastatic melanoma cells. We screened protein tyrosine phosphatases (PTPs) required for TPA-mediated inhibition of cell proliferation. We identified two PTPs, SH2 domain-containing protein tyrosine phosphatase2 (SH-PTP2/PTPN11) and T-cell protein tyrosine phosphatase (TC-PTP/PTPN2), which play key roles in TPA-mediated inhibition of metastatic melanoma cell growth. Transient expression of SH-PTP2 and TC-PTP induced G0/G1 cell cycle arrest in a phosphatase-dependent manner. Furthermore, SH-PTP2 was translocated to the cell membrane upon TPA treatment, resulting in a decrease in Janus kinase 2 (JAK2) activity. TC-PTP is localized in the nucleus together with the adapter protein ubiquitin-like protein 4A (UBL4A/GdX); TC-PTP was translocated to the nuclear periphery upon TPA stimulation. These two signaling pathways, involving SH-PTP2 and TC-PTP, are distinct from those observed in normal melanocytes and benign melanoma cells. These pathways represent previously unknown responses to TPA specific to metastatic melanoma cells. Overall, these findings may contribute to the development of new anticancer agents.