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

Chen, Ni; Chen, Xueqin; Huang, Rui; Zeng, Hao; Gong, Jing; Wei, Meng; Lu, Yiping; Zhao, Fen; Wang, Lin; Zhou, Qiao

doi:10.1074/jbc.m805997200

Cited by 154 publications

(153 citation statements)

References 36 publications

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“…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.…”

Section: Discussioncontrasting

confidence: 92%

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Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

et al. 2010

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Hypoxia-inducible factors (HIFs) provoke adaptation to hypoxic stress occurring in rapidly growing tumor tissues. Therefore, overexpression of HIF-1 or HIF-2 is a common feature in hepatocellular carcinoma but their specific function is still controversially discussed. To analyze HIF function in hypoxia-induced cell death we created a stable knockdown of HIF-1a and HIF-2a in HepG2 cells and generated tumor spheroids as an in vitro hepatocellular carcinoma model. Knockdown of HIF-1a enhanced expression of HIF-2a and vice versa. Unexpectedly, knockdown of HIF-1a or HIF-2a increased cell viability as well as spheroid size and decreased caspase-3 activity. Antiapoptotic Bcl-X L expression increased in both knockdown spheroids, whereas proapoptotic Bax was only reduced in HIF-1a-knockdown cells. Furthermore, an HIF-2a-knockdown significantly increased Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) expression in an HIF-1a-dependent manner. Concomitantly, electron microscopy revealed a substantial increase in autophagosomal structures in HIF-2a-knockdown spheroids and mito-/lysotracker costaining confirmed lysosomal activity of these autophagosomes. Blocking autophagosome maturation using 3-methyladenine restored cell death in HIF-2a-knockdown clones comparable to wildtype cells. Conclusion: An HIF-1a-knockdown increases HIF-2a expression and shifts the balance of Bcl-2 family members toward survival. The knockdown of HIF-2a raises autophagic activity and attenuates apoptosis by enhancing HIF-1a expression. Our data indicate that enhanced expression of one HIF-isoform causes a survival advantage in hepatocellular carcinoma development. (HEPATOLOGY 2010;51:2183-2192

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Section: Discussioncontrasting

confidence: 92%

“…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.…”

mentioning

confidence: 99%

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

et al. 2010

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“…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).…”

Section: Modulation Of the Malignant Behavior Of Pc-initiating Cells mentioning

confidence: 99%

“…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 …”

Section: Modulation Of the Malignant Behavior Of Pc-initiating Cells mentioning

confidence: 99%

“…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).…”

Section: E R E G U L a T E D G E N E P R O D U C T S I N P C S T E mentioning

confidence: 99%

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

Mimeault

Batra

2011

Mol Med

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Recent gene expression profiling analyses and gain-and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC-and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.

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HIF‐1α is an unfavorable determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5‐FU chemotherapy

Nakamura

Kitajima

Kai

et al. 2010

Intl Journal of Cancer

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Among several chemotherapeutic agents, 5-fluorouracil (5-FU) has been widely used as a key drug in adjuvant chemotherapy for gastric cancer. However, no reliable marker, which predicts the response to 5-FU in an adjuvant setting, has been identified. Hypoxia-induced drug resistance, via upregulation of HIF-1a, is a major obstacle in the development of effective cancer therapy. However, few clinical studies have so far assessed the relationship between the HIF-1a expression and the chemo-resistance of gastric cancer patients in an adjuvant setting. We established 2 HIF-1a knockdown gastric cancer cell lines in order to clarify the role of HIF-1a in chemo-resistance against 5-FU. Furthermore, expression of HIF-1a was immunohistochemically assessed in 91 resected specimens. Sixty-four of 91 patients received 5-FU adjuvant chemotherapy after surgery. HIF-1a expression was associated with the significantly shorter relapse-free survival and disease-specific survival in the 64 patients of adjuvant group (p 5 0.026, 0.014, respectively), but not in the 27 of surgery group. Multivariate analysis showed that HIF-1a was an independent risk factor for relapse in 64 patients in the adjuvant group (p 5 0.029). In conclusion, the current study confirmed, for the first time that HIF-1a expression is an independent risk factor for relapse in high-risk gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy. A favorable effect of 5-FU might therefore be expected in patients that do not express HIF-1a, whereas, other types of chemotherapy or additional treatments, such as HIF-1a inhibitors, should be considered in patients that do express HIF-1a.Despite its declining incidence, gastric cancer remains a worldwide health problem that is the fourth most common cancer and the second most frequent cause of cancer-related deaths. 1 Although curative surgery is essential in the treatment of gastric cancer, this single modality treatment seems to have reached its maximal achievable effect for local control and survival. 2 Various regimens of adjuvant chemotherapy, either with or without radiotherapy, have therefore been administered in the hope of preventing a disease relapse and improving the survival rate. [3][4][5] One early meta-analysis concluded that adjuvant chemotherapy did not improve survival, 6 whereas in the last decade, several meta-analyses have confirmed that adjuvant chemotherapy led to statistically significant reductions in mortality and the rate of relapse in comparison to surgery alone. 7-13 However, a consensus regarding a standard regimen has not been obtained among the world.Many drug combinations that include 5-fluorouracil (5-FU), platinum compounds, anthracyclines, taxanes and/or irinotecan have demonstrated promising activity in advanced gastric cancer. Among these chemotherapeutic agents, 5-FU has been widely used as a key drug in adjuvant chemotherapy. Thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are important enzymes in...

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

Cited by 154 publications

References 36 publications

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

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

HIF‐1α is an unfavorable determinant of relapse in gastric cancer patients who underwent curative surgery followed by adjuvant 5‐FU chemotherapy

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