2. Academic Validation
  3. Citrate-Induced p85α⁻PTEN Complex Formation Causes G2/M Phase Arrest in Human Pharyngeal Squamous Carcinoma Cell Lines

Citrate-Induced p85α⁻PTEN Complex Formation Causes G2/M Phase Arrest in Human Pharyngeal Squamous Carcinoma Cell Lines

  • Int J Mol Sci. 2019 Apr 29;20(9):2105. doi: 10.3390/ijms20092105.
Kuang-Chen Hung 1 2 3 4,  Shyang-Guang Wang 5,  Meng-Liang Lin 6,  Shih-Shun Chen 7
Affiliations

Affiliations

  • 1 Division of Neurosurgery, Department of Surgery, Taichung Army Force General Hospital, Taichung 41152, Taiwan. [email protected].
  • 2 Department of Surgery, National Defense Medical Center, Taipei 11490, Taiwan. [email protected].
  • 3 General Education Center, College of Humanities and General Education, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan. [email protected].
  • 4 Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan. [email protected].
  • 5 Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan. [email protected].
  • 6 Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan. [email protected].
  • 7 Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung 40601, Taiwan. [email protected].
PMID: 31035650 DOI: 10.3390/ijms20092105
Abstract

Citrate is a key intermediate of the tricarboxylic acid cycle and acts as an allosteric signal to regulate the production of cellular ATP. An elevated cytosolic citrate concentration inhibits growth in several types of human Cancer cells; however, the underlying mechanism by which citrate induces the growth arrest of Cancer cells remains unclear. The results of this study showed that treatment of human pharyngeal squamous carcinoma (PSC) cells with a growth-suppressive concentration of citrate caused cell cycle arrest at the G2/M phase. A coimmunoprecipitation study demonstrated that citrate-induced cell cycle arrest in the G2/M phase was associated with stabilizing the formation of cyclin B1-phospho (p)-cyclin-dependent kinase 1 (CDK1) (Thr 161) complexes. The citrate-induced increased levels of cyclin B1 and G2/M phase arrest were suppressed by the Caspase-3 inhibitor Ac-DEVD-CMK and Caspase-3 cleavage of mutant p21 (D112N). Ectopic expression of the constitutively active form of protein kinase B (Akt1) could overcome the induction of p21 cleavage, cyclin B1-p-CDK1 (Thr 161) complexes, and G2/M phase arrest by citrate. p85α-phosphatase and tensin homolog deleted from chromosome 10 (PTEN) complex-mediated inactivation of Akt was required for citrate-induced G2/M phase cell cycle arrest because PTEN short hairpin RNA or a PTEN Inhibitor (SF1670) blocked the suppression of Akt Ser 473 phosphorylation and the induction of cyclin B1-p-CDK1 (Thr 161) complexes and G2/M phase arrest by citrate. In conclusion, citrate induces G2/M phase arrest in PSC cells by inducing the formation of p85α-PTEN complexes to attenuate Akt-mediated signaling, thereby causing the formation of cyclin B1-p-CDK1 (Thr 161) complexes.

Keywords

Akt; CDK1; G2/M; PTEN; citrate; cyclin B1; p85α.

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