Gossypetin Inhibits Solar-UV Induced Cutaneous Basal Cell Carcinoma Through Direct Inhibiting PBK/TOPK Protein Kinase.

Abstract

Skin photoaging, skin inflammation and skin cancer are related with excessive exposure to solar UV. PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK), a member of the serine/threonine protein kinase, which regulates the signaling cascades of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal regulated kinase 1/2 (ERK1/2). PBK/TOPK plays a significant role in solar-UV-induced cutaneous basal cell carcinoma (BCC), and targeting PBK/TOPK can be supposed to treat and prevent cutaneous BCC. The pathological feature and the expression level of PBK/TOPK in cutaneous BCC tissues of human were studied in clinical samples. SUV-induced the phosphorylation of p38 MAPK and ERK1/2 were demonstrated ex vivo. Moreover, the interaction between Gossypetin and PBK/TOPK were detected by in vitro kinase assay and Microscale thermophoresis (MST) assay. Furthermore, the effect of Gossypetin to solar UV-induced the activity of PBK/TOPK were detected ex vivo and in vivo. The clinical samples showed that the expression levels of PBK/TOPK, phosphor-p38 MAPK and phosphor- ERK1/2 were up-regulated in cutaneous BCC tissues of human. The expression of phosphor-p38 MAPK or phosphor-ERK1/2 increased in a dose and time dependent manner after solar UV treatment in HaCaT cells. MTT cytotoxicity assay results showed that Gossypetin has no effect on HaCaT cells. In vitro kinase assay and MST assay results showed that Gossypetin bound with PBK/TOPK and suppressed PBK/TOPK activity. Ex vivo results showed Gossypetin inhibited solar UV-induced phosphorylation of PBK/TOPK, p38 MAPK, ERK1/2 and H2AX by suppressing PBK/TOPK activity. In vivo test results indicated that Gossypetin suppressed solar UV-induced increase of PBK/TOPK, phosphor-p38 MAPK, phosphor-ERK1/2 and phosphor- H2AX in SKH-1 hairless mice. Our data demonstrated that Gossypetin can alleviate solar-UV-induced cutaneous BCC by blocking PBK/TOPK, and Gossypetin could be a remarkable agent for treating solar-UV induced cutaneous basal cell carcinoma.