miRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc

Abstract

The proto-oncogene c-Myc plays substantial role in multiple myeloma (MM) pathogenesis and is considered a potential drug target. Here we provide evidence of a novel mechanism for PRIMA-1^Met, a small molecule with anti-tumor activity in phase I/II clinical trial, showing that PRIMA-1^Met induces apoptosis in MM cells by suppressing c-Myc and upregulating miRNA-29a. Our study further demonstrates that miRNA-29a functions as a tumor suppressor which targets c-Myc. The baseline expression of miR-29a was significantly lower in MM cell lines and MM patient samples compared to normal hematopoietic cells. In addition, ectopic expression of miRNA-29a or exposure to PRIMA-1^Met reduced cell proliferation and induced apoptosis in MM cells. On the other hand, overexpression of c-Myc at least partially reverted the inhibitory effects of PRIMA-1^Met or miRNA-29a overexpression suggesting the miRNA-29a/c-Myc axis mediates anti-myeloma effects of PRIMA-1^Met. Importantly, intratumor delivery of miRNA-29a mimics induced regression of tumors in mouse xenograft model of MM and this effect synergized with PRIMA-1^Met. Our study indicates that miRNA-29a is a tumor suppressor that plays an important role during PRIMA-1^Met-induced apoptotic signaling by targeting c-Myc and provides the basis for novel therapeutic strategies using miRNA-29a mimics combined with PRIMA-1^Met in MM.