Lovastatin induced Kruppel like factor 2 ( KLF2 ), Kruppel like factor 6 ( KLF6 ) and Ras homolog family member B ( RHOB ) genes and preferentially led to viability reduction of Cisplatin-resistant cells

// Chiho Koi 1 , Hiroto Izumi 2 , Tomoko Kurita 1 , Thuy Thi Nguyen 1 , Midori Murakami 1 , Yukiko Yoshiura 2 , Toru Hachisuga 1 and Yasuo Morimoto 2 1 Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 805-8555, Japan 2 Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 805-8555, Japan Correspondence to: Hiroto Izumi, email: h-izumi@med.uoeh-u.ac.jp Keywords: statin; cisplatin resistance; KLF; RHOB; HMG-CoA Received: July 22, 2017      Accepted: October 27, 2017      Published: November 16, 2017 ABSTRACT 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, KLF2 , KLF6 , and RHOB , 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 RHOB 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.