RRC ID 67310
Author Tsubaki M, Takeda T, Tomonari Y, Mashimo K, Koumoto YI, Hoshida S, Itoh T, Imano M, Satou T, Sakaguchi K, Nishida S.
Title The MIP-1α autocrine loop contributes to decreased sensitivity to anticancer drugs.
Journal J Cell Physiol
Abstract Several autocrine soluble factors, including macrophage inflammatory protein-1α (MIP-1α), tumor necrosis factor-α, and hepatocyte growth factor, promote cell survival and growth in multiple myeloma (MM) cells. We hypothesized that inhibition of the MIP-1α autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines. In the present study, an MIP-1α neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of melphalan or bortezomib on MM cells. In addition, melphalan resistance cells (RPMI8226/L-PAM and HS-sultan/L-PAM cells) secreted MIP-1α and neutralizing antibody of MIP-1α partially overcame melphalan resistance. Moreover, combination treatment with MIP-1α neutralizing antibody and melphalan or bortezomib inhibited extracellular signal regulated kinase 1/2 (ERK1/2), Akt, and mammalian target of rapamycin (mTOR) activation, Bcl-2, Bcl-xL, and Survivin expression, and upregulated the expression of Bim and cleaved Poly (ADP-ribose) polymerase (PARP). Treatment of IM9 cells with MIP-1α siRNA suppressed the activation of ERK1/2, Akt, and mTOR, and enhanced the cytotoxic effect of melphalan and bortezomib. These results indicate that MIP-1α neutralizing antibodies or MIP-1α siRNA enhance the cytotoxic effect of melphalan and bortezomib by suppressing the chemokine receptor/ERK and chemokine receptor/Akt/mTOR pathways. The inhibition of MIP-1α may thus provide a new therapeutic approach to control tumor progression and bone destruction in patients with MM.
Volume 233(5)
Pages 4258-4271
Published 2018-5-1
DOI 10.1002/jcp.26245
PMID 29057477
MeSH Bortezomib / pharmacology Cell Line, Tumor Cell Proliferation / drug effects* Cell Survival / drug effects Chemokine CCL3 / genetics* Drug Resistance, Neoplasm / genetics* Gene Expression Regulation, Neoplastic / drug effects Humans Melphalan / pharmacology Multiple Myeloma / drug therapy* Multiple Myeloma / genetics Multiple Myeloma / pathology Osteoclasts / drug effects Osteoclasts / metabolism Proto-Oncogene Proteins c-bcl-2 / genetics Survivin / genetics TOR Serine-Threonine Kinases / genetics Tumor Necrosis Factor-alpha / genetics bcl-X Protein / genetics
IF 5.546
Human and Animal Cells RPMI8226(RCB3010)