Loss of p21Cip1/CDKN1A renders cancer cells susceptible to Polo-like kinase 1 inhibition.

Abstract

The deregulation of Polo-like kinase 1 is inversely linked to the prognosis of patients with diverse human tumors. Targeting Polo-like kinase 1 has been widely considered as one of the most promising strategies for molecular anticancer therapy. While the preclinical results are encouraging, the clinical outcomes are rather less inspiring by showing limited anticancer activity. It is thus of importance to identify molecules and mechanisms responsible for the sensitivity of Polo-like kinase 1 inhibition. We have recently shown that p21Cip1/CDKN1A is involved in the regulation of mitosis and its loss prolongs the mitotic duration accompanied by defects in chromosome segregation and cytokinesis in various tumor cells. In the present study, we demonstrate that p21 affects the efficacy of Polo-like kinase 1 inhibitors, especially Poloxin, a specific inhibitor of the unique Polo-box domain. Intriguingly, upon treatment with Polo-like kinase 1 inhibitors, p21 is increased in the cytoplasm, associated with anti-apoptosis, DNA repair and cell survival. By contrast, deficiency of p21 renders tumor cells more susceptible to Polo-like kinase 1 inhibition by showing a pronounced mitotic arrest, DNA damage and apoptosis. Furthermore, long-term treatment with Plk1 inhibitors induced fiercely the senescent state of tumor cells with functional p21. We suggest that the p21 status may be a useful biomarker for predicting the efficacy of Plk1 inhibition.

• Authors: Nina-Naomi Kreis, Frank Louwen, Brigitte Zimmer, Juping Yuan
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 9 Pg. 6611-26 (Mar 30 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25483104 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzoates
• CDKN1A protein, human
• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Quinones
• poloxin
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzoates (pharmacology)
• Cell Cycle Checkpoints (drug effects)
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Cell Survival (drug effects)
• Cellular Senescence (drug effects)
• Colonic Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cyclin-Dependent Kinase Inhibitor p21 (deficiency, genetics)
• DNA Damage
• Dose-Response Relationship, Drug
• Down-Regulation
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• Humans
• Inhibitory Concentration 50
• Molecular Targeted Therapy
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Quinones (pharmacology)
• RNA Interference
• Signal Transduction (drug effects)
• Time Factors
• Transfection