Open AccessmiRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc
Author(s) -
Manujendra N. Saha,
Jahangir Abdi,
Yijun Yang,
Hong Chang
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.6880
Subject(s) - apoptosis , microrna , oncogene , medicine , cancer research , multiple myeloma , hematology , cell cycle , biology , oncology , immunology , cancer , genetics , gene
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-1Met, a small molecule with anti-tumor activity in phase I/II clinical trial, showing that PRIMA-1Met 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-1Met 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-1Met or miRNA-29a overexpression suggesting the miRNA-29a/c-Myc axis mediates anti-myeloma effects of PRIMA-1Met. Importantly, intratumor delivery of miRNA-29a mimics induced regression of tumors in mouse xenograft model of MM and this effect synergized with PRIMA-1Met. Our study indicates that miRNA-29a is a tumor suppressor that plays an important role during PRIMA-1Met-induced apoptotic signaling by targeting c-Myc and provides the basis for novel therapeutic strategies using miRNA-29a mimics combined with PRIMA-1Met in MM.