Heme oxygenase-1 inhibition mediates Gas6 to enhance bortezomib-sensitivity in multiple myeloma via ERK/STAT3 axis
Open Access
- 16 April 2020
- journal article
- research article
- Published by Impact Journals, LLC in Aging
- Vol. 12 (8), 6611-6629
- https://doi.org/10.18632/aging.102996
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.Keywords
This publication has 45 references indexed in Scilit:
- MERTK receptor tyrosine kinase is a therapeutic target in melanomaJCI Insight, 2013
- Heme oxygenase-2/adiponectin protein–protein interaction in metabolic syndromeBiochemical and Biophysical Research Communications, 2013
- Multiple MyelomaNew England Journal of Medicine, 2011
- Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myelomaBlood, 2010
- Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6Blood, 2010
- Mechanisms of Cell Protection by Heme Oxygenase-1Annual Review of Pharmacology and Toxicology, 2010
- Differential Expression of Axl and Gas6 in Renal Cell Carcinoma Reflecting Tumor Advancement and SurvivalClinical Cancer Research, 2009
- Growth arrest-specific gene 6 expression in human breast cancerBritish Journal of Cancer, 2008
- TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human CancerAdvances in Cancer Research, 2008
- International Staging System for Multiple MyelomaJournal of Clinical Oncology, 2005