Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy.
Institute of Biophysics, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
Sci Rep. 2017 Dec 20;7(1):17949. doi: 10.1038/s41598-017-18186-0.
MiR-34a acts as tumor suppressor microRNA (miRNA) in several cancers, including multiple myeloma (MM), by controlling the expression of target proteins involved in cell cycle, differentiation and apoptosis. Here, we have investigated the combination between miR-34a and γ-secretase inhibitor (γSI), Sirtinol or zoledronic acid (ZOL) in order to enhance the inhibitory action of this miRNA on its canonical targets such as Notch1 and SIRT1, and on Ras/MAPK-dependent pathways. Our data demonstrate that miR-34a synthetic mimics significantly enhance the anti-tumor activity of all the above-mentioned anti-cancer agents in RPMI 8226 MM cells. We found that γSI enhanced miR-34a-dependent anti-tumor effects by activating the extrinsic apoptotic pathway which could overcome the cytoprotective autophagic mechanism. Moreover, the combination between miR-34a and γSI increased the cell surface calreticulin (CRT) expression, that is well known for triggering anti-tumor immunological response. The combination between miR-34a and Sirtinol induced the activation of an intrinsic apoptotic pathway along with increased surface expression of CRT. Regarding ZOL, we found a powerful growth inhibition after enforced miR-34a expression, which was not likely attributable to neither apoptosis nor autophagy modulation. Based on our data, the combination of miR-34a with other anti-cancer agents appears a promising anti-MM strategy deserving further investigation.
miR-34a 在多种癌症中作为肿瘤抑制 miRNA（miRNA）发挥作用，包括多发性骨髓瘤（MM），通过控制参与细胞周期、分化和凋亡的靶蛋白的表达。在这里，我们研究了 miR-34a 与 γ-分泌酶抑制剂（γSI）、Sirtinol 或唑来膦酸（ZOL）的联合使用，以增强该 miRNA 对其典型靶标如 Notch1 和 SIRT1 以及 Ras/MAPK 依赖性途径的抑制作用。我们的数据表明，miR-34a 合成模拟物显著增强了 RPMI 8226 MM 细胞中所有上述抗癌剂的抗肿瘤活性。我们发现，γSI 通过激活外在凋亡途径增强了 miR-34a 依赖性的抗肿瘤作用，该途径可以克服细胞保护自噬机制。此外，miR-34a 和 γSI 的联合使用增加了细胞表面钙网蛋白（CRT）的表达，这是触发抗肿瘤免疫反应的已知机制。miR-34a 和 Sirtinol 的联合使用诱导了内在凋亡途径的激活，同时增加了 CRT 的表面表达。关于 ZOL，我们发现强制表达 miR-34a 后会产生强大的生长抑制作用，这可能不是由于凋亡或自噬调节引起的。基于我们的数据，miR-34a 与其他抗癌剂的联合使用似乎是一种很有前途的抗 MM 策略，值得进一步研究。
