AI Article Synopsis

  • * Researchers used a genetic mouse model to show that RACK1 deficiency prevents AKT activation and reduces the formation of prostate tumors linked to the loss of PTEN and p53.
  • * Unlike direct targeting of the PI3K/AKT pathway, inhibiting RACK1 does not cause compensatory activation of other pathways like HER3 or androgen receptor, highlighting its potential as a new therapeutic target in prostate cancer.

Article 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.

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http://dx.doi.org/10.1038/s41388-024-03224-9DOI Listing

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