Koi Chiho, Izumi Hiroto, Kurita Tomoko, Nguyen Thuy Thi, Murakami Midori, Yoshiura Yukiko, Hachisuga Toru, Morimoto Yasuo
Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 805-8555, Japan.
Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 805-8555, Japan.
Oncotarget. 2017 Nov 16;8(63):106429-106442. doi: 10.18632/oncotarget.22472. eCollection 2017 Dec 5.
It was reported that statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase that are used to prevent hypercholesterolemia, have antitumor activity in several cancers. In this study, we investigated the cell viability of statins in Cisplatin-resistant HCP4 and PCDP5 cells compared with their parent Hela and PC3 cells, respectively, and found that HCP4 and PCDP5 cells were 37-fold and 18-fold more resistant to Cisplatin but 13-fold and 7-fold more sensitive to Lovastatin by cell proliferation assay. Lovastatin induced the apoptosis of HCP4 cells more rapidly and to greater extent than in Hela cells as assessed by flow cytometry and western blotting analyses. The MVA pathway was not involved in this acquired Cisplatin resistance. To elucidate the mechanism underlying the reduced viability to Lovastatin, we performed cDNA microarray analysis and identified 65 and 54 genes that were induced more than 2-fold by Lovastatin in HCP4 and PCDP5 cells, respectively. Of these, only three genes, , , and , were commonly induced between HCP4 and PCDP5 cells. These mRNAs were strongly induced by Lovastatin with transcriptional regulation in HCP4 cells. Consistent with transcription, the protein expression of also was induced by Lovastatin. The induction of these genes was associated with cell cycle arrest and apoptosis. Combination treatment with Cisplatin and Lovastatin resulted in an agonistic effect in Hela and PC3 cells and an antagonistic effect in HCP4 and PCDP5 cells. These results suggest that statins might have the potential to overcome Cisplatin resistance as single-agent therapy.
据报道，他汀类药物是用于预防高胆固醇血症的3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，在几种癌症中具有抗肿瘤活性。在本研究中，我们分别研究了他汀类药物在顺铂耐药的HCP4和PCDP5细胞中的细胞活力，并与其亲本Hela和PC3细胞进行比较，通过细胞增殖试验发现HCP4和PCDP5细胞对顺铂的耐药性分别是其亲本细胞的37倍和18倍，但对洛伐他汀的敏感性分别是其亲本细胞的13倍和7倍。通过流式细胞术和蛋白质印迹分析评估，洛伐他汀诱导HCP4细胞凋亡的速度比Hela细胞更快，程度更大。甲羟戊酸（MVA）途径与这种获得性顺铂耐药无关。为了阐明对洛伐他汀活力降低的潜在机制，我们进行了cDNA微阵列分析，分别鉴定出在HCP4和PCDP5细胞中被洛伐他汀诱导超过2倍的65个和54个基因。其中，只有三个基因，即[此处原文缺失基因名称]，在HCP4和PCDP5细胞中共同被诱导。这些mRNA在HCP4细胞中通过转录调控被洛伐他汀强烈诱导。与转录一致，[此处原文缺失蛋白名称]的蛋白表达也被洛伐他汀诱导。这些基因的诱导与细胞周期停滞和凋亡有关。顺铂和洛伐他汀联合治疗在Hela和PC3细胞中产生协同作用，而在HCP4和PCDP5细胞中产生拮抗作用。这些结果表明，他汀类药物作为单药治疗可能具有克服顺铂耐药性的潜力。
