miR-15a enhances the anticancer effects of cisplatin in the resistant non-small cell lung cancer cells
Platinum-based chemotherapies have long been used as a standard treatment in non-small cell lung cancer. However, cisplatin resistance is a major problem that restricts the use of cisplatin. Deregulated cell death mechanisms including apoptosis and autophagy could be responsible for the development of cisplatin resistance and miRNAs are the key regulators of these mechanisms. We aimed to analyse the effects of selected miRNAs in the development of cisplatin resistance and found that hsa-miR-15a-3p was one of the most significantly downregulated miRNAs conferring resistance to cisplatin in Calu1 epidermoid lung carcinoma cells. Only hsa-miR-15a-3p mimic transfection did not affect cell proliferation or cell death, though decreased cell viability was found when combined with cisplatin. We found that induced expression of hsa-miR-15a-3p via mimic transfection sensitised cisplatin-resistant cells to apoptosis and autophagy. Our results demonstrated that the apoptosis- and autophagy-inducing effects of hsa-miR-15a-3p might be due to suppression of BCL2, which exhibits a major connection with cell death mechanisms. This study provides new insights into the mechanism of cisplatin resistance due to silencing of the tumour suppressor hsa-miR-15a-3p and its possible contribution to apoptosis, autophagy and cisplatin resistance, which are the devil’s triangle in determining cancer cell fate.
KeywordsNon-small cell lung cancer Cisplatin resistance Autophagy Apoptosis hsa-miR-15a-3p
This study was supported by the Ege University Research Fund [grant number BAP-2013-TIP-049 (to V.B.Ç.)]. The authors wish to thank Oguz Gözen (Department of Physiology, Ege University Medical Faculty) for proofreading and major contributions to the manuscript.
Conflicts of interest
- 7.Lin K, Farahani M, Yang Y, Johnson GG, Oates M, Atherton M, et al. Loss of MIR15A and MIR16-1 at 13q14 is associated with increased TP53 mRNA, de-repression of BCL2 and adverse outcome in chronic lymphocytic leukaemia. Br J Haematol. 2014;167(3):346–55. doi: 10.1111/bjh.13043.CrossRefPubMedGoogle Scholar
- 40.Bandi N, Zbinden S, Gugger M, Arnold M, Kocher V, Hasan L, et al. miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Res. 2009;69(13):5553–9. doi: 10.1158/0008-5472.CAN-08-4277.CrossRefPubMedGoogle Scholar