Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases.
Open accessAbstract
Activation of androgen receptor (AR) may have a role in the development of castration-resistant prostate cancer. Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. However, the upstream signals that activate these kinases and lead to AR activation are incompletely characterized. In this study, we investigated AR phosphorylation in response to non-androgen ligand stimulation using phospho-specific antibodies. Treatment of LNCaP and LAPC-4 cells with epidermal growth factor (EGF), heregulin, Gas6 (ligand binding to the Mer receptor tyrosine kinase and activating Ack1 downstream), interleukin (IL)-6 or bombesin stimulated cell proliferation in the absence of androgen. Treatment of LNCaP and LAPC-4 cells with EGF, heregulin or Gas6 induced AR phosphorylation at Tyr-267, whereas IL-6 or bombesin treatment did not. AR phosphorylation at Tyr-534 was induced by treatment with EGF, IL-6 or bombesin, but not by heregulin or Gas6. Small interfering RNA-mediated knockdown of Ack1 or Src showed that Ack1 mediates heregulin- and Gas6-induced AR Tyr-267 phosphorylation, whereas Src mediates Tyr-534 phosphorylation induced by EGF, IL-6 and bombesin. Dasatinib, a Src inhibitor, blocked EGF-induced Tyr-534 phosphorylation. In addition, we showed that dasatinib also inhibited Ack1 kinase. Dasatinib inhibited heregulin-induced Ack1 kinase activity and AR Tyr-267 phosphorylation. In addition, dasatinib inhibited heregulin-induced AR-dependent reporter activity. Dasatinib also inhibited heregulin-induced expression of endogenous AR target genes. Dasatinib inhibited Ack1-dependent colony formation and prostate xenograft tumor growth in castrated mice. Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF-induced AR Tyr-267 phosphorylation or EGF-stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr-267. These data suggest that specific tyrosine kinases phosphorylate AR at distinct sites and that dasatinib may exert antitumor activity in prostate cancer through inhibition of Ack1.
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Treatment of LNCaP and LAPC-4 cells with bombesin/gastrin-releasing peptide (GRP) in the absence of androgen induces AR phosphorylation at Tyr-534 via Src activation and induces subsequent AR-mediated transcription.
“Treatment of LNCaP and LAPC-4 cells with GRP in the absence of androgen induces AR phosphorylation at Tyr-534, via Src activation, and induces subsequent AR-mediated transcription (28).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [28]
In prostate cancer cells that express endogenous AR, such as LNCaP and LAPC-4, treatment with EGF in the absence of androgen induces phosphorylation of the AR at Tyr-267 and -534 by Src and Ack1 kinases.
“In prostate cancer cells that express endogenous AR, such as LNCaP and LAPC-4, treatment with EGF in the absence of androgen induces phosphorylation of the AR at Tyr-267 and -534 by Src and Ack1 kinases (28).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [28]
Activated Src can phosphorylate the AR at Tyr-534, thereby promoting its transcriptional activity in LNCaP and LAPC-4 cells.
“Activated Src can phosphorylate AR at Tyr-534, thereby promoting its transcriptional activity in LNCaP and LAPC-4 cells (27,28).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [28]
Heregulin/neuregulin (NRG-1) and growth-arrest specific 6 (Gas-6) treatment also induce AR phosphorylation and activity through activation of the Cdc42-related kinase Ack1.
“This effect is similar to that of other growth factors such as heregulin/neuregulin (NRG-1) and growth-arrest specific 6 (Gas-6) (a ligand for the Mer receptor tyrosine kinase; named for its expression in monocytes and tissues of epithelial and reproductive origin) treatment, which also induce AR phosphorylation and activity, through activation of the Cdc42-related kinase Ack1 (28).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [28]
LNCaP xenografts that overexpress ectopic Ack1 demonstrate significantly increased growth in castrated mice, which is inhibited by the kinase inhibitor dasatinib.
“LNCaP xenografts that overexpress ectopic Ack1 demonstrate significantly increased growth in castrated mice, which is inhibited by the kinase inhibitor dasatinib (28).”
From Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer (2011) · cites this paper as [28]
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- Authors
- Liu, Y., Karaca, M., Zhang, Z., Gioeli, D., Earp, H. S., & Whang, Y. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of Virginia Health System (US)
- Corresponding author
- Whang, Y E
- Venue
- Oncogene
- Published
- 2010-04-12
- Volume
- 29
- Issue
- 22
- Pages
- 3208-3216
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC2880659
- OpenAlex
- W2004037338
- Cited by
- 106
- References
- 35
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 1 · 2022: 11 · 2021: 5 · 2020: 7 · 2019: 5 · 2018: 4 · 2017: 1 · 2016: 9 · 2015: 6 · 2014: 18 · 2013: 15 · 2012: 8
- FWCI
- 8.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Bristol-Myers Squibb
- National Institutes of Health
- National Cancer Institute (NIH R01CA120921, NIH R01CA120304, R01CA120921, R01CA124706, R01CA120304)
- National Institute of Environmental Health Sciences (NIH T32ES007017, T32ES007017)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- dasatinib, androgen receptor, tyrosine phosphorylation, ACK1, Src kinase, castration-resistant prostate cancer, neuregulin-1, epidermal growth factor, Gas6, interleukin-6, bombesin, kinase inhibition, LNCaP cells, LAPC4 cells
- MeSH terms
- Dasatinib, Animals, Chlorocebus aethiops, Humans, Male, Phosphorylation, Prostatic Neoplasms, Protein-Tyrosine Kinases, Pyrimidines, Receptors, Androgen, Thiazoles, Transfection, Immunoblotting, Signal Transduction, src-Family Kinases, COS Cells, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Growth Processes, Mice, Androgen Receptor Antagonists
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