A novel HIF-1α-integrin-linked kinase regulatory loop that facilitates hypoxia-induced HIF-1α expression and epithelial-mesenchymal transition in cancer cells
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// Chih-Chien Chou 1 , Hsaio-Ching Chuang 1 , Santosh B. Salunke 1 , Samuel K. Kulp 1 , Ching-Shih Chen 1, 2 1 Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA 2 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan Correspondence to: Ching-Shih Chen, e-mail: chen.844@osu.edu Keywords: Hypoxia-inducible factor-1α, integrin-linked kinase, epithelial-mesenchymal transition, YB-1, Foxo3a Received: November 24, 2014 Accepted: January 23, 2015 Published: March 16, 2015 ABSTRACT Here, we described a novel regulatory feedback loop in which hypoxia induces integrin-linked kinase (ILK) expression through a HIF-1α-dependent mechanism and ILK, in turn, stimulates HIF-1α expression through cell type- and cell context-dependent pathways. HIF-1α increased ILK via transcriptional activation. ILK increased HIF-1α levels by promoting mTOR-mediated translation in PC-3 and MCF-7 cells, and by blocking GSK3β-mediated degradation in LNCaP cells, consistent with the cell line-/cellular context-specific functions of ILK as a Ser473-Akt kinase. We show that ILK can account for the effects of hypoxia on Akt, mTOR, and GSK3β phosphorylation. Also, ILK can de-repress HIF-1α signaling through the YB-1-mediated inhibition of Foxo3a expression. In concert with HIF-1α, these downstream effectors promote epithelial-mesenchymal transition (EMT) through modulation of Snail and Zeb1. Thus, the ILK-HIF-1α regulatory loop could underlie the maintenance of high HIF-1α expression levels and the promotion of EMT under hypoxic conditions. Finally, we show that the small-molecule ILK inhibitor T315 can disrupt this regulatory loop in vivo and suppress xenograft tumor growth, thereby providing proof-of-concept that targeting ILK represents an effective strategy to block HIF-1α expression and aggressive phenotype in cancer cells.
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The HIF pathway indirectly promotes EMT through Notch, TGF-β, integrin-linked kinase, certain tyrosine kinase receptors, Wnt, and Hedgehog.
“The HIF pathway also indirectly promotes EMT through a number of cell signaling pathways, including Notch (74, 75), TGF-β (76), integrin-linked kinase (77), certain tyrosine kinase receptors (48), Wnt (73), and Hedgehog (78, 79).”
From Hypoxic control of metastasis (2016) · cites this paper as [77]
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References 59 · Cited by 50
- Authors
- Chou, C.-C., Chuang, H.-C., Salunke, S. B., Kulp, S. K., & Chen, C.-S.
- Affiliations
- The Ohio State University (US)
- Institute of Biological Chemistry, Academia Sinica (TW)
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2015-03-16
- Volume
- 6
- Issue
- 10
- Pages
- 8271-8285
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC4480751
- OpenAlex
- W1522368007
- Cited by
- 50
- References
- 59
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 13 · 2015: 5
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA112250)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- HIF-1α, integrin-linked kinase, epithelial-mesenchymal transition, hypoxia, feedback regulatory loop, YB-1, FOXO3, Akt signaling, snails, ZEB1, cancer stemness, tumor growth inhibition, prostate cancer, breast cancer
- MeSH terms
- Scaffold Protein ILK, Animals, Breast Neoplasms, Female, Humans, Male, Mice, Nude, Prostatic Neoplasms, Transfection, Signal Transduction, Cell Hypoxia, Protein Serine-Threonine Kinases, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Epithelial-Mesenchymal Transition, MCF-7 Cells, Heterografts
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