Department of Dermatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Department of Biochemistry and Molecular Biology, Basic Medical Science of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
Anticancer Agents Med Chem. 2019;19(8):1029-1036. doi: 10.2174/1871520619666190301123131.
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.
皮肤光老化、皮肤炎症和皮肤癌与过度暴露于太阳紫外线有关。PDZ 结合激酶/T-LAK 细胞起源蛋白激酶（PBK/TOPK）是丝氨酸/苏氨酸蛋白激酶家族的一员，调节 p38 丝裂原活化蛋白激酶（p38 MAPK）和细胞外信号调节激酶 1/2（ERK1/2）的信号级联反应。PBK/TOPK 在太阳紫外线诱导的皮肤基底细胞癌（BCC）中起着重要作用，靶向 PBK/TOPK 可以用于治疗和预防皮肤 BCC。
在临床样本中研究了人类皮肤 BCC 组织中 PBK/TOPK 的病理特征和表达水平。在体外用 SUV 诱导 p38 MAPK 和 ERK1/2 的磷酸化。此外，通过体外激酶测定和微量热泳动（MST）测定检测了牡荆素与 PBK/TOPK 的相互作用。此外，还在体外用和体内检测了牡荆素对太阳紫外线诱导的 PBK/TOPK 活性的影响。
临床样本显示，人类皮肤 BCC 组织中 PBK/TOPK、磷酸化 p38 MAPK 和磷酸化 ERK1/2 的表达水平上调。在 HaCaT 细胞中，太阳紫外线处理后，p38 MAPK 或 ERK1/2 的表达呈剂量和时间依赖性增加。MTT 细胞毒性测定结果表明牡荆素对 HaCaT 细胞没有影响。体外激酶测定和 MST 测定结果表明，牡荆素与 PBK/TOPK 结合并抑制 PBK/TOPK 活性。在体实验结果表明，牡荆素通过抑制 PBK/TOPK 活性抑制太阳紫外线诱导的 PBK/TOPK、p38 MAPK、ERK1/2 和 H2AX 的磷酸化。体内试验结果表明，牡荆素抑制了 SKH-1 无毛小鼠中太阳紫外线诱导的 PBK/TOPK、磷酸化 p38 MAPK、磷酸化 ERK1/2 和磷酸化 H2AX 的增加。
我们的数据表明，牡荆素通过阻断 PBK/TOPK 缓解太阳紫外线诱导的皮肤 BCC，牡荆素可能是治疗太阳紫外线诱导的皮肤基底细胞癌的一种显著药物。
