miRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc
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Manujendra N. Saha1,2,*,†, Jahangir Abdi1,2,*, Yijun Yang1,2,3, Hong Chang1,2,4
1Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Ontario, Canada
2Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
3Department of Applied Chemistry, School of Chemical Engineering and Technology, Tianjin University, Tianjin, P. R. China
4Department of Laboratory Hematology and Medical Oncology, University Health Network, Toronto, Ontario, Canada
†Current address: Department of Surgery, London Health Sciences Center, London, Ontario, Canada
*These authors have contributed equally to this work
Hong Chang, e-mail: [email protected]
Keywords: myeloma, miRNA-29a, Myc, apoptosis
Received: September 03, 2015 Accepted: January 03, 2016 Published: January 11, 2016
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.
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