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Tumor cells upregulate normoxic HIF-1α in response to doxorubicin.

Publication ,  Journal Article
Cao, Y; Eble, JM; Moon, E; Yuan, H; Weitzel, DH; Landon, CD; Nien, CY-C; Hanna, G; Rich, JN; Provenzale, JM; Dewhirst, MW
Published in: Cancer Res
October 15, 2013

Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that controls cellular homeostasis. Although its activation benefits normal tissue, HIF-1 activation in tumors is a major risk factor for angiogenesis, therapeutic resistance, and poor prognosis. HIF-1 activity is usually suppressed under normoxic conditions because of rapid oxygen-dependent degradation of HIF-1α. Here, we show that, under normoxic conditions, HIF-1α is upregulated in tumor cells in response to doxorubicin, a chemotherapeutic agent used to treat many cancers. In addition, doxorubicin enhanced VEGF secretion by normoxic tumor cells and stimulated tumor angiogenesis. Doxorubicin-induced accumulation of HIF-1α in normoxic cells was caused by increased expression and activation of STAT1, the activation of which stimulated expression of iNOS and its synthesis of nitric oxide (NO) in tumor cells. Mechanistic investigations established that blocking NO synthesis or STAT1 activation was sufficient to attenuate the HIF-1α accumulation induced by doxorubicin in normoxic cancer cells. To our knowledge, this is the first report that a chemotherapeutic drug can induce HIF-1α accumulation in normoxic cells, an efficacy-limiting activity. Our results argue that HIF-1α-targeting strategies may enhance doxorubicin efficacy. More generally, they suggest a broader perspective on the design of combination chemotherapy approaches with immediate clinical impact.

Duke Scholars

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

October 15, 2013

Volume

73

Issue

20

Start / End Page

6230 / 6242

Location

United States

Related Subject Headings

  • Up-Regulation
  • Transcription Factors
  • STAT1 Transcription Factor
  • Random Allocation
  • Oncology & Carcinogenesis
  • Nitric Oxide Synthase Type II
  • Nitric Oxide
  • Mice, Nude
  • Mice
  • Mammary Neoplasms, Experimental
 

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Cao, Y., Eble, J. M., Moon, E., Yuan, H., Weitzel, D. H., Landon, C. D., … Dewhirst, M. W. (2013). Tumor cells upregulate normoxic HIF-1α in response to doxorubicin. Cancer Res, 73(20), 6230–6242. https://doi.org/10.1158/0008-5472.CAN-12-1345
Cao, Yiting, Joseph M. Eble, Ejung Moon, Hong Yuan, Douglas H. Weitzel, Chelsea D. Landon, Charleen Yu-Chih Nien, et al. “Tumor cells upregulate normoxic HIF-1α in response to doxorubicin.Cancer Res 73, no. 20 (October 15, 2013): 6230–42. https://doi.org/10.1158/0008-5472.CAN-12-1345.
Cao Y, Eble JM, Moon E, Yuan H, Weitzel DH, Landon CD, et al. Tumor cells upregulate normoxic HIF-1α in response to doxorubicin. Cancer Res. 2013 Oct 15;73(20):6230–42.
Cao, Yiting, et al. “Tumor cells upregulate normoxic HIF-1α in response to doxorubicin.Cancer Res, vol. 73, no. 20, Oct. 2013, pp. 6230–42. Pubmed, doi:10.1158/0008-5472.CAN-12-1345.
Cao Y, Eble JM, Moon E, Yuan H, Weitzel DH, Landon CD, Nien CY-C, Hanna G, Rich JN, Provenzale JM, Dewhirst MW. Tumor cells upregulate normoxic HIF-1α in response to doxorubicin. Cancer Res. 2013 Oct 15;73(20):6230–6242.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

October 15, 2013

Volume

73

Issue

20

Start / End Page

6230 / 6242

Location

United States

Related Subject Headings

  • Up-Regulation
  • Transcription Factors
  • STAT1 Transcription Factor
  • Random Allocation
  • Oncology & Carcinogenesis
  • Nitric Oxide Synthase Type II
  • Nitric Oxide
  • Mice, Nude
  • Mice
  • Mammary Neoplasms, Experimental