RETRACTED: Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

Lee, Kang Ae; Qian, David Z.; Rey, Sergio; Wei, Hong; Liu, Jun O.; Semenza, Gregg L.

doi:10.1073/pnas.0812801106

Cited by 273 publications

(220 citation statements)

References 25 publications

(40 reference statements)

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“…A recent screening of a library of drugs identified doxorubicin and daunorubicin as potent inhibitors of hypoxia-inducible gene induction. Daily administration of DXR to tumor-bearing mice reduced the expression of HIF target, angiogenic genes in tumor xenografts, and the recruitment of circulating bone marrow-derived angiogenic cells (32). These results are consistent with ours and lend support to our proposal that DXR dampens HIF response in vivo.…”

Section: Discussionsupporting

confidence: 91%

Anthracycline Inhibits Recruitment of Hypoxia-inducible Transcription Factors and Suppresses Tumor Cell Migration and Cardiac Angiogenic Response in the Host

Tanaka

Yamaguchi

Shoji

et al. 2012

Journal of Biological Chemistry

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Background:Anthracycline is an antitumor agent of the topoisomerase inhibitor family. Results: Doxorubicin inhibits the expression of hypoxia-inducible genes, suppresses HIF-dependent migration of target tumors, and dampens angiogenic response of the host heart. Conclusion: Doxorubicin blocks recruitment of HIF heterodimers to the enhancer and inhibits hypoxia response. Significance: The pleiotropic effect of doxorubicin on HIF signaling provides a clue for understanding efficacy and toxicity of cancer chemotherapy.

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Section: Discussionsupporting

confidence: 91%

Anthracycline Inhibits Recruitment of Hypoxia-inducible Transcription Factors and Suppresses Tumor Cell Migration and Cardiac Angiogenic Response in the Host

Tanaka

Yamaguchi

Shoji

et al. 2012

Journal of Biological Chemistry

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“…DXR, an anthracycline anticancer agent, exhibits cytotoxicity that intercalates DNA and induces TOPII-mediated strand breaks (59). A recent convincing and meaningful report (60) proposed evidence that HIF1 binds to hypoxia-responsive elements (HREs), which are cis-acting DNA sequences containing the consensus binding site to mediate HIF-inducible and -dependent transcription; moreover, anthracyclines disrupt the binding of HIF1 to HREs in vitro and probably in vivo.…”

Section: Expression Of Several Proteins Related To Glycogen Metabolismentioning

confidence: 99%

Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

et al. 2012

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Abstract. Ovarian clear cell carcinoma (OCCC) has several significant characteristics based on molecular features that are distinct from those of ovarian high-grade serous carcinoma. Cellular glycogen accumulation is the most conspicuous feature of OCCC and in the present study its metabolic mechanism was investigated. The amount of glycogen in cells cultured under hypoxia increased significantly and approximately doubled after 48 h (P<0.01) compared to that under normoxic conditions. Periodic acid-Schiff positive staining also demonstrated intracellular glycogen storage. Western blot analysis revealed that HIF1α, which was overexpressed and stabilized under hypoxic conditions, led to an increase in the levels of cellular glycogen synthase 1, muscle type (GYS1), and conversely to a decrease in inactive phosphorylated GYS1 at serine (Ser) 641. Additional increases were observed in both protein phosphatase 1, which dephosphorylates and thereby induces GYS1 enzyme activity, and glycogen synthase kinase 3 beta (GSK3β) phosphorylated at Ser9, which is inactive on phosphorylation of GYS1 and subsequently induces its enzyme activity. By contrast, the level of PYGM-b decreased. These results indicated that the glycogen accumulation under a hypoxic environment resulted in the promotion of glycogen synthesis, but did not lead to inhibition of glycogen degradation and/or consumption. Under hypoxic conditions, HAC2 cells showed activation of the PI3K/AKT pathway caused by a mutation in exon 20 of PIK3CA, encoding the catalytic subunit p110α of PI3K. The resulting activation of AKT (phosphoSer473) also plays a role as a central enhancer in glycogen synthesis through suppression of GSK3β via phosphorylation at Ser9. Hypoxia decreased the cytocidal activity of cisplatin and doxorubicin to various degrees. In conclusion, the hypoxic conditions together with HIF1 expression and stabilization increased the intracellular glycogen contents and resistance to the anticancer drugs.

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“…Several antitumor agents including EF24 (curcumin analog), 13 glucosamine, 14 apigenin, 15 quercetin, 16 NS398 (Cox-2 inhibitor), 17 doxorubicin (anthracyclin), 18 trichostatin A (histone deacetylase inhibitor) 19 and rapamycin (mTOR inhibitor) 20 have been shown to inhibit HIF-1a in numerous cancer cell types including those of the prostate. These agents may lead to decreased HIF-1a DNA binding, decreased HIF-1a synthesis or decreased HIF-1a transactivation.…”

mentioning

confidence: 99%

Methylseleninic acid downregulates hypoxia‐inducible factor‐1α in invasive prostate cancer

Sinha

Null

Wolter

et al. 2011

Intl Journal of Cancer

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Alternative strategies are needed to control growth of advanced and hormone refractory prostate cancer. In this regard, we investigated the efficacy of methylseleninic acid (MSeA), a penultimate precursor to the highly reactive selenium metabolite, methylselenol, to inhibit growth of invasive and hormone refractory rat (PAIII) and human (PC-3 and PC-3M) prostate cancer cells. Our results demonstrate that MSeA inhibits PAIII cell growth in vitro as well as reduces weights of tumors generated by PAIII cells treated ex vivo. A significant reduction in the number of metastatic lung foci by MSeA treatment was also noted in Lobund-Wistar rats. The PAIII cells along with PC-3, DU145 and PC-3M cells undergo apoptosis after MSeA treatments in both normoxia and hypoxia. Treatment of metastatic rat and human prostate cancer cell lines with MSeA decreased hypoxiainducible factor-1a (HIF-1a) levels in a dose-dependent manner. Additionally, HIF-1a transcription activity both in normoxic and hypoxic conditions is reduced after MSeA treatment of prostate cancer cells. Furthermore, VEGF and GLUT1, downstream targets of HIF-1a, were also reduced in prostate cancer cells after MSeA treatment. Our study illustrates the efficacy of MSeA in controlling growth of hormone refractory prostate cancer by downregulating HIF-1a, which is possibly occurring through stabilization or increase in prolyl hydroxylase activity.In men with advanced prostate cancer, hormone therapy is accepted as the initial treatment of choice and produces good responses in most patients. However, many patients relapse and become resistant to further hormone manipulation. Radical prostatectomy is recommended for treatment of localized prostate cancer. Unfortunately, local recurrences occur in up to one-third of patients by 5 years after surgery.1 Furthermore, a combination of hormone therapy with radical prostatectomy in patients with localized disease resulted in 5-year disease-free survival of 64%. 2Effective radiation therapy requires the presence of oxygen.3 As a result of rapid mitotic growth and clonal expansion, tumor cells are usually forced away from vessels beyond effective diffusion distance of oxygen and thrive remarkably well within a hypoxic environment. This tumor hypoxia may lead to resistance to radiation and chemotherapy.4 Hypoxia within solid tumors induces hypoxia-inducible factor (HIF)-1a, 5 and its elevation in prostate cancer cells may attribute to enhanced growth rates, survival and increased metastatic potential. 6HIF-1 is a heterodimer composed of an inducible a-subunit that confers the sensitivity to oxygen and a constitutively expressed b-subunit, aryl hydrocarbon receptor nuclear translocator.7 Under normoxic conditions after a post-translational hydroxylation by prolyl hydroxylase (PHD), HIF-1a interacts with tumor suppressor von-Hippel-Lindau protein and is rapidly degraded via ubiquitin-dependent proteasome pathway. 8 Hypoxia induces a rapid increase in HIF-1a protein stability and transcriptional activity, 9 resulting in the activat...

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RETRACTED: Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

Cited by 273 publications

References 25 publications

Anthracycline Inhibits Recruitment of Hypoxia-inducible Transcription Factors and Suppresses Tumor Cell Migration and Cardiac Angiogenic Response in the Host

Anthracycline Inhibits Recruitment of Hypoxia-inducible Transcription Factors and Suppresses Tumor Cell Migration and Cardiac Angiogenic Response in the Host

Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

Methylseleninic acid downregulates hypoxia‐inducible factor‐1α in invasive prostate cancer

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