Premium
The MIP‐1α autocrine loop contributes to decreased sensitivity to anticancer drugs
Author(s) -
Tsubaki Masanobu,
Takeda Tomoya,
Tomonari Yoshika,
Mashimo Kenji,
Koumoto Yuichi,
Hoshida Sachi,
Itoh Tatsuki,
Imano Motohiro,
Satou Takao,
Sakaguchi Katsuhiko,
Nishida Shozo
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26245
Subject(s) - bortezomib , autocrine signalling , cytotoxic t cell , pi3k/akt/mtor pathway , protein kinase b , cancer research , mapk/erk pathway , chemistry , pharmacology , biology , immunology , signal transduction , receptor , multiple myeloma , in vitro , biochemistry
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.