Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan, Republic of China.
Department of Biochemistry, National Defense Medical Center, Taipei City, Taiwan, Republic of China.
PLoS One. 2019 Apr 2;14(4):e0214408. doi: 10.1371/journal.pone.0214408. eCollection 2019.
p21, an inhibitor of cyclin-dependent kinase, functions as an oncogene or tumor suppressor depending on the context of a variety of extracellular and intracellular signals. The expression of p21 could be regulated at the transcriptional and/or post-translational levels. The p21 gene is well-known to be regulated in both p53-dependent and -independent manners. However, the detailed regulatory mechanisms of p21 messenger RNA and protein expression via statins remain unknown, and the possible application of statins as anticancer reagents remains to be controversial. Our data showed that the statins-fluvastatin and lovastatin-induced p21 expression as general histone deacetylase inhibitors in a p53-independent manner, which is mediated through various pathways, such as apoptosis, autophagy, cell cycle progression, and DNA damage, to be involved in the function of p21 in HeLa cells. The curative effect repositioning of digoxin, a cardiovascular medication, was combined with fluvastatin and lovastatin, and the results further implied that p21 induction is involved in a p53-dependent and p53-independent manner. Digoxin modified the effects of statins on ATF3, p21, p53, and cyclin D1 expression, while fluvastatin boosted its DNA damage effect and lovastatin impeded its DNA damage effect. Fluvastatin and lovastatin combined with digoxin further support the localization specificity of their interactivity with our subcellular localization data. This study will not only clarify the regulatory mechanisms of p21 induction by statins but will also shed light on the repurposing of widely cardiovascular medications for the treatment of cervical cancer.
p21 是细胞周期蛋白依赖性激酶的抑制剂，其作为癌基因或肿瘤抑制因子的功能取决于各种细胞外和细胞内信号的情况。p21 的表达可以在转录和/或翻译后水平上进行调节。众所周知，p21 基因受 p53 依赖性和非依赖性方式的调节。然而，他汀类药物通过何种机制调节 p21 信使 RNA 和蛋白表达仍不清楚，他汀类药物作为抗癌试剂的可能应用仍然存在争议。我们的数据表明，他汀类药物——氟伐他汀和洛伐他汀以非 p53 依赖性方式诱导 p21 表达，作为一般组蛋白去乙酰化酶抑制剂，这是通过多种途径介导的，如细胞凋亡、自噬、细胞周期进程和 DNA 损伤，涉及 p21 在 HeLa 细胞中的功能。心血管药物地高辛的治疗作用再定位与氟伐他汀和洛伐他汀联合使用，结果进一步表明，p21 的诱导涉及 p53 依赖性和非依赖性方式。地高辛改变了他汀类药物对 ATF3、p21、p53 和细胞周期蛋白 D1 表达的影响，而氟伐他汀增强了其 DNA 损伤作用，洛伐他汀则阻碍了其 DNA 损伤作用。氟伐他汀和洛伐他汀与地高辛联合使用进一步支持了它们与我们亚细胞定位数据相互作用的定位特异性。本研究不仅阐明了他汀类药物诱导 p21 的调节机制，也为广泛的心血管药物治疗宫颈癌的再利用提供了思路。
