A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation
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Michela Restelli1, Martina Magni1, Vincenzo Ruscica2
1Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milan 20133, Italy.
Abstract:
Human CCAR2 has recently emerged as having a pivotal role in the DNA damage response, promoting apoptosis and repair of heterochromatic DNA breaks. However, less is known about the function of CCAR2 in tumor formation and cancer progression. Here, we demonstrate, for the first time, that CCAR2 loss inhibits the proliferation of cancer cells, but preserves the growth of normal cells. Investigating the mechanisms responsible for this differential effect, we found that CCAR2 depletion specifically impairs the activation of AKT pathway in cancer cells, but not in normal cells, by reducing AKT phosphorylation on Ser473. This effect is achieved through the transcriptional upregulation of TRB3 gene and accumulation of TRB3 protein, which then binds to and inhibits the phosphorylation and activation of AKT. The defective activation of AKT finally results in reduced GSK3β phosphorylation, prevention of G1/S transition and inhibition of cancer cell growth. These results establish an important role for CCAR2 in cancer cells proliferation and could shed new light on novel therapeutic strategies against cancer, devoid of detrimental side effects.
Insights
Loss of CCAR2 inhibits cancer cell proliferation by disrupting the AKT pathway, while sparing normal cells. This discovery offers potential for targeted cancer therapies with fewer side effects.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Human CCAR2 is recognized for its role in DNA damage response, including apoptosis and heterochromatic DNA break repair.
- The specific function of CCAR2 in tumor formation and cancer progression remains largely unexplored.
Purpose of the Study:
- To investigate the role of CCAR2 in cancer cell proliferation and identify the underlying molecular mechanisms.
- To determine if CCAR2's function differs between cancer and normal cells.
Main Methods:
- CCAR2 depletion in cancer and normal cell lines.
- Analysis of AKT pathway activation, including AKT and GSK3β phosphorylation.
- Assessment of TRB3 gene expression and protein levels.
- Cell cycle analysis (G1/S transition).
Main Results:
- CCAR2 loss inhibited cancer cell proliferation but preserved normal cell growth.
- CCAR2 depletion specifically impaired AKT pathway activation in cancer cells by reducing AKT phosphorylation at Ser473.
- This impairment was mediated by the transcriptional upregulation of TRB3, leading to increased TRB3 protein accumulation and subsequent inhibition of AKT.
- Defective AKT activation resulted in reduced GSK3β phosphorylation, G1/S cell cycle arrest, and inhibited cancer cell growth.
Conclusions:
- CCAR2 plays a critical role in cancer cell proliferation through the regulation of the AKT/TRB3/GSK3β axis.
- Targeting CCAR2 could offer a therapeutic strategy for cancer treatment with a potentially reduced side-effect profile on normal cells.
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