TIG1 Inhibits the mTOR Signaling Pathway in Malignant Melanoma Through the VAC14 Protein.

Abstract

Currently, there are few drug options available to treat malignant melanoma. Tazarotene-inducible gene 1 (TIG1) was originally isolated from skin tissue, but its function in skin tissue has not been clarified. The aim of this study was to elucidate the effect of TIG1 and mTOR signaling pathways associated with VAC14 on melanoma. The expression of TIG1 and VAC14 in melanoma tissue was analyzed using a melanoma tissue cDNA array. The interaction between TIG1 and VAC14 was analyzed using immunoprecipitation and immunostaining. Western blot was used to investigate the molecular targets of TIG1 and VAC14 in melanoma cells. TIG1 was highly expressed in normal skin tissue but was low in malignant melanoma, while VAC14 showed the opposite trend. TIG1 inhibited insulin-induced cell proliferation and insulin-activated mammalian target of rapamycin complex 1 (mTORC1)-p70 S6 kinase but did not affect the level of phospho-AKT in A2058 melanoma cells. This suggests that the main target of TIG1 regulating cell growth is phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] rather than the PI(4,5)P2 signaling pathway. Additional TIG1 showed no additive effect on the inhibition of mTOR signaling in the absence of VAC14 expression, suggesting that TIG1 inhibited the activation of mTOR mainly by inhibiting VAC14. TIG1 may play an important role in preventing malignant melanoma through retinoic acid via VAC14.