Journal article
Unveiling RACK1: a key regulator of the PI3K/AKT pathway in prostate cancer development
Oncogene, Vol.44(5), pp.322-335
02/18/2025
DOI: 10.1038/s41388-024-03224-9
PMCID: PMC13006131
PMID: 39537875
Abstract
The dysregulated PI3K/AKT pathway is pivotal in the onset and progression of various cancers, including prostate cancer. However, targeting this pathway directly poses challenges due to compensatory upregulation of alternative oncogenic pathways. This study focuses on the novel regulatory activity of the Receptor for Activated Protein Kinase (RACK1), a scaffolding/adaptor protein, in governing the PI3K/AKT pathway within prostate cancer. Through a genetic mouse model, our research unveils RACK1's pivotal role in orchestrating AKT activation and the genesis of prostate cancer. RACK1 deficiency hampers AKT activation, effectively impeding prostate tumor formation induced by PTEN and p53 deficiency. Mechanistically, RACK1 facilitates AKT membrane translocation and fosters its interaction with mTORC2, thereby promoting AKT activation and subsequent tumor cell proliferation and tumor formation. Notably, inhibiting AKT activation via RACK1 deficiency does not trigger feedback upregulation of HER3 and androgen receptor (AR) expression and activation, distinguishing it from direct PI3K or AKT targeting. These findings position RACK1 as a critical regulator of the PI3K/AKT pathway and a promising target for curtailing prostate cancer development arising from pathway aberrations.The dysregulated PI3K/AKT pathway is pivotal in the onset and progression of various cancers, including prostate cancer. However, targeting this pathway directly poses challenges due to compensatory upregulation of alternative oncogenic pathways. This study focuses on the novel regulatory activity of the Receptor for Activated Protein Kinase (RACK1), a scaffolding/adaptor protein, in governing the PI3K/AKT pathway within prostate cancer. Through a genetic mouse model, our research unveils RACK1's pivotal role in orchestrating AKT activation and the genesis of prostate cancer. RACK1 deficiency hampers AKT activation, effectively impeding prostate tumor formation induced by PTEN and p53 deficiency. Mechanistically, RACK1 facilitates AKT membrane translocation and fosters its interaction with mTORC2, thereby promoting AKT activation and subsequent tumor cell proliferation and tumor formation. Notably, inhibiting AKT activation via RACK1 deficiency does not trigger feedback upregulation of HER3 and androgen receptor (AR) expression and activation, distinguishing it from direct PI3K or AKT targeting. These findings position RACK1 as a critical regulator of the PI3K/AKT pathway and a promising target for curtailing prostate cancer development arising from pathway aberrations.
Details
- Title: Subtitle
- Unveiling RACK1: a key regulator of the PI3K/AKT pathway in prostate cancer development
- Creators
- Cancan Lyu - University of IowaPrasanna Kuma Vaddi - University of IowaSaid Elshafae - University of IowaAnirudh Pradeep - University of IowaDeqin Ma - University of IowaSonghai Chen - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.44(5), pp.322-335
- DOI
- 10.1038/s41388-024-03224-9
- PMID
- 39537875
- PMCID
- PMC13006131
- NLM abbreviation
- Oncogene
- ISSN
- 1476-5594
- eISSN
- 1476-5594
- Publisher
- SPRINGERNATURE
- Grant note
- U.S. Department of Health & Human Services | National Institutes of Health (NIH): R01CA207889, R01CA282699, 1S10OD026835-01 National Institutes of Health
We would like to thank Dr. Michael Henry for providing us the Pb-Cre4-PTENfl/fl/PTENfl/fl mice. The work was partially supported by funding from National Institutes of Health grant R01CA207889 (SC) and R01CA282699 (SC), and National Institutes of Health shared instrumentation grant (1S10OD026835-01) for the small animal imaging core.
- Language
- English
- Electronic publication date
- 11/13/2024
- Date published
- 02/18/2025
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9984748256102771
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