Abstract
Interactions between bone marrow stromal cells (BMSCs) and multiple myeloma cells significantly contribute to the progression of multiple myeloma (MM). However, little is known about the molecular mechanisms that regulate these interactions. Connexin-43 (Cx-43) has been implicated in the interplay between BMSCs and MM cells. In this study, we hypothesized that the steroid receptor co-activator-3 (SRC3) expressed in BMSCs regulates the expression of Cx-43 to promote the proliferation and migration of myeloma cells. To address this, we co-cultured a human multiple myeloma cell line, RPMI-8226 transfected with either control BMSCs or sh-SRC3-BMSCs. We found that knocking down SRC3 expression in BMSCs inhibited the proliferation and migration of RPMI-8226 cells. In addition, we found that co-culturing RPMI 8266 cells with BMSCs increased Cx43 expression, while knocking down SRC3 expression in BMSCs decreased Cx43 expression. Moreover, our work revealed that SRC3 in BMSCs regulates Cx43 expression via the mitogen-activated protein kinase (MAPK) pathway. To validate this result in vivo, we knocked down SRC3 expression in BMSCs in nude mice and found that tumor growth and cell apoptosis were significantly decreased. In addition, mice treated with either RPMI 8266 cells overexpressing Cx43 or with a P38 MAPK inhibitor (SB202190) exhibited increased intratumoral leukocyte populations and promoted cell apoptosis in tumor tissue. Our findings demonstrate how SRC3 and Cx43 regulation between BMSCs and myeloma cells mediate cell growth and disease progression, with potential implications for prognosis and therapeutic interventions.