The Function Of NFAT3 In Melanoma And Its Role As A Therapeutic Target

Melanoma is the most malignant subtype of skin cancer,which has a high mortality rate and accounts for nearly four-fifths of skin cancer death.In 2012,there were 203,200 new cases of melanoma worldwide,killing 55,000 people.At present,the main strategies for skin cancer treatment are surgery or chemotherapy,but the traditional therapies have limited effects and significant side effects.Therefore,discovering potential targets involved in the carcinogenesis and development of skin cancer and then developing targeted drugs becomes an important issue for clinical melanoma treatment.Nuclear factor of activated T cells(NFAT)family is a class of transcription factors which can regulate the expression of pro-inflammatory cytokine and other genes in the immune respone.In addition to immune cells,they have been found expressed in muscles,bones,neurons,internal organs and skin,and associated with cancer closely.Comparing with other NFAT family members,the function of NFAT3 is rarely studied in cancers and the limited results are still controversial.At present,the function of NFAT3 in melanoma is unknown.Both tacrolimus(FK506)and ascomycin(FK520)are anti-immunological rejection drugs after organ transplantation with the similar chemical structures.They play immunosuppressive effects through innhibiting the activity of calcineurin(Ca N),then reducing the dephosphorylated level of NFAT protein,and inhibiting its translocation into the nucleus.At present,FK506 was used in a variety of pre-clinical cancer research as a potential anti-cancer drug for bladder cancer,prostate cancer,breast cancer and so on.FK506 acting on the melanogenesis of melanoma cells is also reported.But there is neither FK520 and melanoma treatment-related research,nor the study of the correlation between NFAT3 and FK506?FK520.Basing on our previous studies of NFAT3,we detected the expression of NFAT3 in several melanoma cell lines and then selected A375 and SK-MEL-28 melanoma cell lines,with high NFAT3 expression,to construct NFAT3-knockdown stable cell lines and carry out the functional experiments.We found that the growth and migration of melanoma was inhibited by knocking down the NFAT3 expression.The result suggested that NFAT3 acts as an oncogenic factor in melanoma.Subsequently,human melanoma cells A375,SK-MEL-28 were treated with FK506 or FK520.The results showed that both FK506 and FK520 can inhibit the cell growth and migration.Further experiments demonstrated that both FK506 and FK520 affected NFAT3 nuclear distribution by inhibiting NFAT3 localization.Finally,the inhibitory effect of FK506 and FK520 on melanoma was studied in vivo through tumor-bearing nude mice models.In conclusion,NFAT3 which plays an oncogenic role during melanoma progression is a potential target for melanoma treatment.Both FK506 and FK520 can suppress melanoma cell proliferation,migration partially inhibiting the function of NFAT3.