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Independence of HIF1a and androgen signaling pathways in prostate cancer.

Published version
Peer-reviewed

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Type

Article

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Authors

Tran, Maxine GB 
Bibby, Becky AS 
Yang, Lingjian 
Lo, Franklin 
Warren, Anne Y 

Abstract

BACKGROUND: Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated. METHODS: In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq. RESULTS: Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic. CONCLUSIONS: The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted.

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Keywords

Androgen signaling, HIF1a signaling, Hypoxia, Prostate cancer, Androgen Antagonists, Androgens, Animals, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Mice, Prostatic Neoplasms, Receptors, Androgen, Signal Transduction, Transcriptional Activation, Tumor Cells, Cultured, Xenograft Model Antitumor Assays

Journal Title

BMC Cancer

Conference Name

Journal ISSN

1471-2407
1471-2407

Volume Title

20

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (096956/Z/11/Z)