Miyajima Chiharu, Hayakawa Yurika, Inoue Yasumichi, Nagasaka Mai, Hayashi Hidetoshi
Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
Department of Innovative Therapeutics Sciences, Cooperative Major in Nanopharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
Pharmaceuticals (Basel). 2022 Aug 17;15(8):1015. doi: 10.3390/ph15081015.
Transcriptional coactivator with PDZ-binding motif (TAZ) is a downstream transcriptional regulator of the Hippo pathway that controls cell growth and differentiation. The aberrant activation of TAZ correlates with a poor prognosis in human cancers, such as breast and colon cancers. We previously demonstrated that TAZ inhibited the tumor suppressor functions of p53 and enhanced cell proliferation. Statins, which are used to treat dyslipidemia, have been reported to suppress the activity of TAZ and exert anti-tumor effects. In the present study, we focused on the regulation of p53 functions by TAZ and investigated whether statins modulate these functions via TAZ. The results obtained suggest that statins, such as simvastatin and fluvastatin, activated the transcriptional function of p53 by suppressing TAZ protein expression. Furthermore, co-treatment with simvastatin and anti-tumor agents that cooperatively activate p53 suppressed cancer cell survival. These results indicate a useful mechanism by which statins enhance the effects of anti-tumor agents through the activation of p53 and may represent a novel approach to cancer therapy.
含PDZ结合基序的转录共激活因子（TAZ）是Hippo信号通路的下游转录调节因子，可控制细胞生长和分化。TAZ的异常激活与人类癌症（如乳腺癌和结肠癌）的不良预后相关。我们之前证明TAZ抑制p53的肿瘤抑制功能并促进细胞增殖。他汀类药物用于治疗血脂异常，据报道可抑制TAZ的活性并发挥抗肿瘤作用。在本研究中，我们聚焦于TAZ对p53功能的调节，并研究他汀类药物是否通过TAZ调节这些功能。所得结果表明，辛伐他汀和氟伐他汀等他汀类药物通过抑制TAZ蛋白表达激活p53的转录功能。此外，辛伐他汀与协同激活p53的抗肿瘤药物联合治疗可抑制癌细胞存活。这些结果表明了一种有用的机制，即他汀类药物通过激活p53增强抗肿瘤药物的作用，这可能代表了一种新的癌症治疗方法。
