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Research Paper|Volume 12, Issue 8|pp 6611—6629

Heme oxygenase-1 inhibition mediates Gas6 to enhance bortezomib-sensitivity in multiple myeloma via ERK/STAT3 axis

Zhaoyuan Zhang1,2,3, Weili Wang2,4, Dan Ma1,2,3, Jie Xiong1,2,3, Xingyi Kuang1,2,3, Siyu Zhang2,4, Qin Fang4, Jishi Wang1,2,3
  • 1Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
  • 2Key Laboratory of Hematological Disease Diagnostic and Treat Centre of Guizhou Province, Guiyang 550004, China
  • 3Guizhou Province Hematopoietic Stem Cell Transplantation Centre, Guiyang 550004, China
  • 4Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
Received: December 27, 2019Accepted: February 20, 2020Published: April 16, 2020
https://doi.org/10.18632/aging.102996

Copyright © 2020 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Chemoresistance is still a critical challenge for efficient treatment of multiple myeloma (MM) during the bortezomib-based chemotherapy. Recent studies have suggested that heme oxygenase-1 (HO-1) is involved in apoptosis, proliferation and chemoresistance in cancer cells. Here we aim to investigate the role and mechanism of HO-1 in bortezomib-sensitivity to myeloma cells. In the study population, we found that HO-1 was highly expressed in CD138+ primary myeloma cells, which was positively associated with Gas6 expression and Gas6 plasma levels in MM patients. Downregulation of HO-1 using pharmacological inhibitor ZnPPIX or siRNA knockdown significantly enhanced myeloma cell sensitivity to bortezomib in human primary CD138+ cells, U266 and RPMI8226 cell lines. Mechanistically, HO-1 regulated Gas6 production via ERK/STAT3 axis. Combination with HO-1 inhibition increased bortezomib-induced apoptosis and antiproliferative effects via suppressing Gas6 production. These findings suggest that combination of bortezomib and HO-1 inhibitor may serve as a promising therapeutic target against bortezomib-resistant MM.