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PAK5-mediated AIF phosphorylation inhibits its nuclear translocation and promotes breast cancer tumorigenesis

Yao Xing1, Yang Li1, Bingtao Hu1

  • 1Department of Cell Biology, Key Laboratory of Cell Biology of National Health Commission of the PRC, Key Laboratory of Medical Cell Biology of Ministry of Education of the PRC, China Medical University, No.77, Puhe Road, Shenyang, 110122, Liaoning, China.

International Journal of Biological Sciences
|April 19, 2021
PubMed

Insights

p21 activated kinase 5 (PAK5) inhibits breast cancer cell death by blocking apoptosis-inducing factor (AIF) nuclear entry. This PAK5-AIF pathway promotes tumor growth and is linked to poor patient prognosis, offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • p21 activated kinase 5 (PAK5) involvement in cancer progression is known, but its role in breast cancer is unclear.
  • Apoptosis-inducing factor (AIF) is crucial for mitochondrial, caspase-independent apoptosis, translocating to the nucleus to induce cell death.

Purpose of the Study:

  • To elucidate the biological function of PAK5 in breast cancer.
  • To investigate the mechanism by which PAK5 influences apoptosis.
  • To determine the clinical significance of the PAK5-AIF pathway in breast cancer.

Main Methods:

  • Investigated PAK5's effect on AIF release and nuclear translocation in breast cancer cells.
  • Analyzed AIF phosphorylation at Thr281 and its impact on AIF/importin α3 complex formation.
  • Assessed the functional role of PAK5-mediated AIF phosphorylation in cell proliferation and tumor growth in vivo.
  • Correlated PAK5 and AIF expression levels with patient prognosis and AIF nuclear translocation.

Main Results:

  • PAK5 inhibits apoptosis by decreasing mitochondrial membrane permeability and increasing membrane potential, thus preventing AIF release.
  • PAK5 phosphorylates AIF at Thr281, inhibiting AIF/importin α3 complex formation and subsequent nuclear translocation.
  • PAK5-mediated AIF phosphorylation promotes breast cancer cell proliferation and in vivo tumor growth.
  • High PAK5 and AIF expression correlate with poor prognosis in breast cancer patients.
  • PAK5 expression is inversely correlated with AIF nuclear translocation.

Conclusions:

  • PAK5 acts as an oncoprotein in breast cancer by inhibiting AIF-mediated apoptosis.
  • The PAK5-AIF signaling pathway is a critical regulator of mammary tumorigenesis.
  • Targeting the PAK5-AIF pathway presents a promising therapeutic strategy for breast cancer treatment.
Keywords:
AIFPAK5apoptosisbreast cancer

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