P-3F, a microtubule polymerization inhibitor enhances P53 stability through the change in localization of RPS27a

- P-3F inhibits microtubule polymerization.
- P-3F leads to cell cycle arrest at G2/M via P53/P21 signaling pathway.
- P-3F enhances P53 stability by inhibiting Mdm2-mediated ubiquitination of P53.
- P-3F blocks P53-Mdm2 feedback loop through the change in localization of RPS27a.

Previously, we demonstrated that P-3F, a podophyllum derivative, exhibits a 297-fold enhancement in antitumor activity than VP-16, used as anticancer agent in clinical. The purpose of our present study was to investigate the precise antitumor mechanism action of P-3F. It showed that P-3F inhibited microtubule polymerization in a concentration-dependent manner. The results were in overall agreement with modeling and docking studies performed on P-3F and tubulin. In addition, P-3F increased the levels of P53, this in turn prolonged P53 half-life. Note as well that levels of P21 protein were increased along with P53 in a concentration dependent change. It suggested that enhancement in stabilization of P53 induced by P-3F may be critical for P53/P21 signaling pathway, resulting in cell cycle arrest at G2/M. Furthermore, release of RPS27a from the nucleolus into the nucleoplasm led to decrease phosphorylation of Mdm2 at serine residue 166 and inhibit Mdm2-mediated ubiquitination of P53 in (P-3F)-treated HeLa cells. Together, these data suggest that P-3F, a microtubule polymerization inhibitor, causes P53 accumulation via P53 stability enhancement, due to blockage of the P53-Mdm2 network through the change in localization of RPS27a.

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