Nimmanapalli Ramadevi, Gerbino Elvira, Dalton William S, Gandhi Varsha, Alsina Melissa
Department of Pathobiology, College of Veterinary Medicine, Tuskegee University, Tuskegee, AL 36088, USA.
Br J Haematol. 2008 Aug;142(4):551-61. doi: 10.1111/j.1365-2141.2008.07217.x. Epub 2008 May 22.
Heat shock proteins (HSPs) are a super family of highly conserved molecular chaperone proteins, which are induced in response to stress. HSP70 has been demonstrated to inhibit apoptosis induced by a number of chemotherapeutic agents. Previous investigations have suggested the development of drug resistance in multiple myeloma (MM) cells after adhesion to stroma. This study used MM cell lines and primary plasma cells to determine if HSP70 had a role in development of chemo resistance. Adhesion of MM cells to either bone marrow stromal cells or fibronectin (FN) enhanced HSP70 expression. Inhibition of the HSP70 expression decreased 8226 cell adhesion to stroma or FN and induced more apoptosis in FN-adhered 8226 cells than in suspension cultures at 24 h. Further, HSP70 inhibitors enhanced melphalan-induced apoptosis and reversed melphalan-induced cell adhesion-mediated drug resistance (CAM-DR) phenotype. In addition, compared to parental cells, KNK-437, a heat shock factor inhibitor caused more apoptosis in melphalan-resistant 8226/LR5 cells and sensitized them to melphalan. Primary CD138 positive cells showed high expression of HSPA4 mRNA, and KNK-437 caused apoptosis in these cells. In conclusion, our data suggest inhibition of HSP70, reduced adhesion and caused apoptosis of both acquired and de novo drug resistant MM cells.
热休克蛋白（HSPs）是一类高度保守的分子伴侣蛋白超家族，其在应激反应中被诱导产生。HSP70已被证明可抑制多种化疗药物诱导的细胞凋亡。先前的研究表明，多发性骨髓瘤（MM）细胞黏附于基质后会产生耐药性。本研究使用MM细胞系和原代浆细胞来确定HSP70在化疗耐药性形成中是否起作用。MM细胞与骨髓基质细胞或纤连蛋白（FN）的黏附增强了HSP70的表达。抑制HSP70的表达可降低8226细胞与基质或FN的黏附，并在24小时时诱导FN黏附的8226细胞比悬浮培养的细胞发生更多凋亡。此外，HSP70抑制剂增强了美法仑诱导的细胞凋亡，并逆转了美法仑诱导的细胞黏附介导的耐药性（CAM-DR）表型。此外，与亲代细胞相比，热休克因子抑制剂KNK-437在美法仑耐药的8226/LR5细胞中引起更多凋亡，并使它们对美法仑敏感。原代CD138阳性细胞显示HSPA4 mRNA高表达，且KNK-437在这些细胞中引起凋亡。总之，我们的数据表明，抑制HSP70可减少黏附，并导致获得性和原发性耐药MM细胞凋亡。
