BCL-xL Is a Target Gene Regulated by Hypoxia-inducible Factor-1α

Abstract

The transcription factor hypoxia-inducible factor-1␣ (HIF-1␣) plays pivotal roles in physiology and pathophysiology. Constitutive or hypoxia-induced HIF-1␣ overexpression is observed in many types of cancers including prostate adenocarcinoma, in which it is associated with resistance to apoptosis and therapeutic agents. BCL-xL, a hypoxia-responsive, anti-apoptotic protein of the Bcl-2 family, is also overexpressed in prostate carcinoma and many other cancers. Despite this connection, whether BCL-xL expression is directly regulated by HIF-1␣ is not known. We used prostate cancer PC-3 cell with constitutive high HIF-1␣ level as a model to address this important question. We first generated prostate cancer PC-3 cells in which HIF-1␣ was stably knocked-down (HIF-KD) by using small interference RNA. BCL-xL was dramatically decreased in HIF-KD PC-3 cells, in parallel with sensitization to apoptosis with caspase-3 activation as well as decreased cell proliferation. We then demonstrated that HIF-1␣ directly regulated BCL-xL transcription by binding to a hypoxia-responsive element in the BCL-xL promoter (؊865 to ؊847) by reporter gene assay, chromatin immunoprecipitation, and electrophoretic mobility shift and supershift assays. HIF-1␣-dependent BCL-xL overexpression may be an important mechanism by which HIF-1␣ protects prostate cancer cells from apoptosis and leads to treatment resistance.

Roles of hypoxia-inducible factor-1α (HIF-1α) versus HIF-2α in the survival of hepatocellular tumor spheroids

“…Reduced apoptosis was attributed to changes in the expression of various Bcl-2 family proteins such Bcl-X L , Bax, and BNIP3. Although Chen et al 8 recently proposed Bcl-X L as an HIF-1-specific target in prostate cancer cells, our data suggest that it is regulated by both HIF-1 and HIF-2 in HepG2 cells. Bcl-X L exerts its antiapoptotic function by antagonizing Bax-induced apoptosis (for review, see Ref.…”

“…They comprise antiapoptotic proteins, i.e., Bcl-2 and Bcl-X L and the proapoptotic proteins Bax and Bak, which were previously linked to HIF-signaling. 8,9 Thus, the balance of these factors is critical for regulation of cell demise. A further properly controlled process that interplays with apoptosis is autophagy, initially related to cell death.…”

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

“…The PC progression is typically associated with the degradation of basal membrane, loss of the basal epithelial cell layer and cell adhesion, intense remodeling changes that occur in the components of tumor-reactive stroma and interactive cross-talks between the PC-initiating cells and their progenies with stromal cells (Figures 1 and 3) (5,43,44,75,76,(130)(131)(132)(133). More specifically, an intense remodeling of diverse ECM components, including an upregulation of integrin receptor ligands, peptidoglycans such as perlecan, and secreted proteolytic enzymes including matrix metalloproteinases (MMPs), urokinasetype plasminogen activator (uPA), matriptase and hepsin as well as a decreased expression of decorin often occurs during PC progression (Figure 2) (5,43,44,134).…”

“…In addition, the induction of tumor hypoxia and vascularization and a decrease of extracellular pH in local tumor microenvironment of PC stem/progenitor cells and their progenies also may alter their metabolic and survival pathways and promote their invasion and metastasis (75,76,(130)(131)(132)(133)141). In fact, PC …”

“…NF-κB, HIF-1α and/or HIF-2α may induce the expression of different target gene products such as glycolytic enzymes, macrophage-inhibitory cytokine-1 (MIC-1), IL-6, cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), P-glycoprotein (P-gp) (also designated as multidrug resistance 1 [MDR-1 or ABCB1]), Bcl-2 and/or Bcl-xL in PC cells under normoxic and hypoxic conditions ( Figure 2) (75,76,(130)(131)(132)141). These gene products in turn may play critical roles in PC progression by upregulating the glycolysis, angiogenic switch, survival pathways and chemoresistance of PC stem/progenitor cells and their progenies (Figure 2) (75,76,(130)(131)(132)(141)(142)(143)(144).…”