Down-regulation of BAG3 inhibits proliferation and promotes apoptosis of glioblastoma multiforme through BAG3/HSP70/HIF-1α signaling pathway

Bcl2-associated athanogene 3 (BAG3) belongs to the BAG family and regulates many biologic behaviors of tumors. When tumor cells are in a hypoxic condition, BAG3 protein expression level increases, as does HIF-1 alpha which is an important transcription factor induced by hypoxia. Glioblastoma is one of the typical solid tumors existing in a hypoxic microenvironment that can activate expression of BAG3 and HIF-1 alpha. This research aimed to reveal the relationship between BAG3 and HIF-1 alpha and their effects in glioblastoma multiforme. We found that down-regulated BAG3 inhibited proliferation and promoted apoptosis of glioblastoma multiforme U87 and U251 cell lines by decreasing HIF-1 alpha expression level. The mechanism of BAG3 regulating HIF-1 alpha is mainly through increasing degradation of HIF-1 alpha by HSP70. When HIF-1 alpha was up-regulated, induced by HIF-1 alpha plasmid transfection on the basis of down-regulation of BAG3, the proliferation inhibition and apoptosis promotion were partially reversed. This novel result showed, for the first time, that down-regulation of BAG3 resulted in a low expression of HIF-1 alpha under both normoxic or hypoxic conditions and finally caused inhibited proliferation and promoted apoptosis in glioblastoma. The mechanism of down-regulated BAG3 decreased HIF-1 alpha protein expression through enhancing formation of HSP70-HIF-1 alpha complex and promoting degradation of HIF-1 alpha by HSP70.