Treatment with siRNA and antisense oligonucleotides targeted to HIF‐1α induced apoptosis in human tongue squamous cell carcinomas

Zhang, Qunzhou; Zhang, Zuo‐Feng; Rao, Jian Yu; Sato, Junichi; Brown, Jimmy J.; Messadi, Diana V.; Le, Anh D.

doi:10.1002/ijc.20334

Cited by 81 publications

(67 citation statements)

References 48 publications

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“…This suspicion is supported by the facts that inhibitors of HIF-1 inhibit tumor growth and enhance the tumor sensitivity to anticancer agents. 36,37 In the present study, however, OSCC cells did not become completely susceptible to chemotherapeutic drugs and g-rays even though the expression of HIF1a was completely knocked down by HIF-1a-siRNA duplexes. This result suggests that many factors other than HIF-1a are involved in the chemo-radio-resistance of cancer cells.…”

Section: Discussioncontrasting

confidence: 66%

The involvement of hypoxia‐inducible factor‐1α in the susceptibility to γ‐rays and chemotherapeutic drugs of oral squamous cell carcinoma cells

Sasabe

Zhou

et al. 2006

Intl Journal of Cancer

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The transcription factor hypoxia-inducible factor-1a (HIF-1a) is the key regulator that controls the hypoxic response of mammalian cells. The overexpression of HIF-1a has been demonstrated in many human tumors. However, the role of HIF-1a in the therapeutic efficacy of chemotherapy and radiotherapy in cancer cells is poorly understood. In this study, we investigated the influence of HIF-1a expression on the susceptibility of oral squamous cell carcinoma (OSCC) cells to chemotherapeutic drugs (cis-diamminedichloroplatinum and 5-fluorouracil) and c-rays. Treatment with chemotherapeutic drugs and c-rays enhanced the expression and nuclear translocation of HIF-1a, and the susceptibility of OSCC cells to the drugs and c-rays was negatively correlated with the expression level of HIF-1a protein. The overexpression of HIF-1a induced OSCC cells to become more resistant to the anticancer agents, and down-regulation of HIF-1a expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF-1a-knockdown OSCC cells, the expression of P-glycoprotein, heme oxygenase-1, manganese-superoxide dismutase and ceruloplasmin were downregulated and the intracellular levels of chemotherapeutic drugs and reactive oxygen species were sustained at higher levels after the treatment with the anticancer agents. These results suggest that enhanced HIF-1a expression is related to the resistance of tumor cells to chemo-and radio-therapy and that HIF-1a is an effective therapeutic target for cancer treatment. ' 2006 Wiley-Liss, Inc.Key words: hypoxia-inducible factor-1a; chemotherapeutic drugs; g-rays; P-glycoprotein; heme oxygenase-1 Solid tumors generally possess hypoxic areas in their central portion because of decreased vascular supply associated with the effects of treatment and the originally increased energy demand of cancer cells, and the hypoxic tissue is one of the serious matters for consideration in the control of malignant tumors. Most tumor cells possess the ability to undergo apoptosis in response to hypoxic conditions. However, tumor cells can adapt to hypoxic conditions by employing a variety of survival tools, which result in the promotion of cancer cell growth and metastasis. [1][2][3] This adaptation of cancer cells to hypoxia is mainly mediated by the transcription factor hypoxia-inducible factor-1 (HIF-1). 4 HIF-1 is a heterodimeric transcription factor consisting of an oxygen-regulated a subunit (HIF1a) and a stable nuclear factor, HIF-1b/aryl hydrocarbon receptor nuclear translocator (ARNT). Under normoxic conditions, HIF-1a is rapidly degraded by the proteosome after being targeted for ubiquitination. HIF-1a translocates to the nucleus under hypoxic conditions and forms an active complex with HIF-1b; the complex binds to the hypoxia-response element (HRE) in the target genes, which results in the transactivation of these genes. 5 Proteins encoded by such genes contribute to the blood supply, energy production, growth/survival, invasion/metastasis and resistance.It has been frequently rep...

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Section: Discussioncontrasting

confidence: 66%

The involvement of hypoxia‐inducible factor‐1α in the susceptibility to γ‐rays and chemotherapeutic drugs of oral squamous cell carcinoma cells

Sasabe

Zhou

et al. 2006

Intl Journal of Cancer

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“…Besides activation of anaerobic metabolism, several Hif-1a-dependent or -independent antiapoptotic mechanisms that all contribute to apoptosis resistance of hypoxic cells have been described. Those mainly include overexpression of antiapoptotic proteins, for example, Bcl-2, Bcl-X L or cIAP-2, or downregulation of proapoptotic proteins such as Bid or Bax (Park et al, 2002;Erler et al, 2004;Zhang et al, 2004). Indeed, we also found upregulation of c-IAP-2 and/or Bcl-2 in A204 RMS and A673 ES Figure 6 Hif-1a-mediated upregulation of GLUT-1 under hypoxia confers apoptosis resistance.…”

Section: N H H-gd A204 A673supporting

confidence: 49%

“…Hif-1a promotes cell death through an increase in p53 or other proapoptotic proteins such as Bcl-2/E1B 19 kDa interacting protein 3 (BNIP3) or BNIP3L (NIX) (Carmeliet et al, 1998;Bruick, 2000;Guo et al, 2001;Sowter et al, 2001). Under most circumstances however, Hif-1a promotes survival of cancer or endothelial cells under hypoxic condition and also protects against apoptosis induced by serum deprivation or by anticancer agents (Alvarez-Tejado, 2001; Sasabe et al, 2005;Piret et al, 2004;Kim et al, 2004a, b;Zhang et al, 2004). Hif-1a exerts its antiapoptotic function by transcriptional activation of antiapoptotic proteins, for example, those of the Bcl-2 family or inhibitor of apoptosis 'IAPs', or by alterations in cellular energy metabolism through increased glucose uptake and glycolysis (Mathupala et al, 2001;Park et al, 2002;Dong et al, 2003;Zhang et al, 2004;Blum et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Under most circumstances however, Hif-1a promotes survival of cancer or endothelial cells under hypoxic condition and also protects against apoptosis induced by serum deprivation or by anticancer agents (Alvarez-Tejado, 2001; Sasabe et al, 2005;Piret et al, 2004;Kim et al, 2004a, b;Zhang et al, 2004). Hif-1a exerts its antiapoptotic function by transcriptional activation of antiapoptotic proteins, for example, those of the Bcl-2 family or inhibitor of apoptosis 'IAPs', or by alterations in cellular energy metabolism through increased glucose uptake and glycolysis (Mathupala et al, 2001;Park et al, 2002;Dong et al, 2003;Zhang et al, 2004;Blum et al, 2005). These data suggest that Hif-1a may promote or protect against apoptosis in response to hypoxia in a cell type-and/or stimulus-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

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Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

et al. 2006

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Hypoxia inducible factor-1 (HIF-1) is the major transcription factor and key regulator of adoptive responses to hypoxia. Although it usually promotes tumor cell survival under hypoxia, it has also been implied to trigger apoptosis. Although the impact of hypoxia has been extensively studied in many adult solid tumors, its role in most childhood tumors, for example, in rhabdomyosarcoma (RMS) or Ewing sarcoma (ES), has not yet been addressed. Here, we report that hypoxia protects A204 RMS and A673 ES cells against anticancer drug-or tumor necrosis factor-related apoptosis-inducing ligandinduced apoptosis and that Hif-1a plays a key role in conferring apoptosis resistance under hypoxia. Although a functional HIF-1 pathway and proapoptotic proteins such as p53 and Bcl-2/E1B 19 kDa interacting protein 3 were activated under hypoxia in both A204 RMS and A673 ES cells, these cells remained refractory to apoptosis. Concomitant analysis of antiapoptotic proteins revealed that hypoxia induced expression of Bcl-2 and inhibitor of apoptosis proteins (IAP)-2 as well as proteins associated with anaerobic metabolism such as the glucose transporter protein GLUT-1 and the glycolytic enzyme Aldolase A. Specific downregulation of Hif-1a by RNA interference significantly enhanced apoptosis under hypoxia by preventing the hypoxia-mediated increase in GLUT-1 expression without altering expression levels of the antiapoptotic proteins Bcl-2 or cIAP-2. Moreover, glucose deprivation-induced apoptosis of A204 RMS and A673 ES cells was inhibited under hypoxic conditions in a Hif-1a-dependent manner. As GLUT-1 was induced via Hif-1a under hypoxia in A204 RMS and A673 ES, these findings suggest that the Hif-1a-mediated increase in glucose uptake plays an important role in conferring apoptosis resistance. Thus, hypoxia-inducible genes may represent novel targets for therapeutic intervention in some pediatric tumors, which warrants further investigation.

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“…Therefore, HIF-1 is an attractive target for cancer therapy. 18 Several approaches have been used to inhibit HIF-1a expression and/or activity, which include antisense or siRNA strategies, 19,20 inhibition of proteins that modulate HIF-1 activity, [21][22][23][24] signal transduction pathways involved in HIF-1a activation [25][26][27] microtubules, topoisomerase I 28 or mechanisms not clearly defined. 29 A number of anticancer drugs have been shown to inhibit HIF, but none of these drugs have been shown to directly and specifically target HIF-1.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1α and induces G2/M arrest under hypoxia in prostate cancer cells

Manohar

Padgaonkar

Jalota‐Badhwar

et al. 2011

Prostate Cancer Prostatic Dis

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BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to oxygen deprivation and controls genes involved in glycolysis, angiogenesis, migration and invasion. Overexpression of HIF-1a has been demonstrated in many common human cancers. METHODS:Luciferase reporter gene assay under hypoxia and normoxia was used to demonstrate transcriptional inhibition of HIF-1 by P276-00. Detailed studies such as western blotting, reverse-transcriptase-PCR and immunofluorescence were carried out to elucidate its mechanism of action. Cytotoxic potential of P276-00 under normoxia and hypoxia was determined on prostate cancer cells using CCK-8 assay, and cell-cycle analysis was carried out using flow cytometry. Antiangiogenic activity of P276-00 was demonstrated by migration assay and tube-formation assay. Efficacy study of P276-00 was performed in a PC-3 xenograft model.RESULTS: P276-00 inhibits transcriptional activation of HIF-1 under hypoxia. It suppressed hypoxia-mediated nuclear HIF-1a expression, as well as phosphorylation of Akt and 4E-BP1 and abrogated expression of HIF-1-inducible gene viz. vascular endothelial growth factor. Under hypoxia, P276-00 did not exhibit enhanced cytotoxic activity in prostate cancer cells but arrested them in the G2/M phase of the cell cycle. The tubular formation of human umbilical vein endothelial cells and migration of prostate cancer cells were also inhibited by P276-00 in vitro. In addition, it demonstrated significant in vivo efficacy in the PC-3 xenograft model. CONCLUSIONS:Given its low toxicity profile, its demonstrated antitumor activity and its potential to inhibit the HIF-1 pathway, P276-00 should be considered as antiangiogenic chemotherapy for prostate cancer.

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Treatment with siRNA and antisense oligonucleotides targeted to HIF‐1α induced apoptosis in human tongue squamous cell carcinomas

Abstract: Overexpression of hypoxia inducible factor-1␣ (HIF-1␣

Cited by 81 publications

References 48 publications

The involvement of hypoxia‐inducible factor‐1α in the susceptibility to γ‐rays and chemotherapeutic drugs of oral squamous cell carcinoma cells

The involvement of hypoxia‐inducible factor‐1α in the susceptibility to γ‐rays and chemotherapeutic drugs of oral squamous cell carcinoma cells

Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

Cyclin-dependent kinase inhibitor, P276-00, inhibits HIF-1α and induces G2/M arrest under hypoxia in prostate cancer cells

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