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.
Highlights
The Cdk-interacting protein p21Cip1/CDKN1A (p21) plays key roles in a broad range of cellular events like cell cycle regulation, apoptosis, differentiation, cytoskeletal dynamics, cell migration, gene transcription, DNA repair, reprogramming of induced pluripotent stem cells, aging and onset of senescence [1]
We show that p21 impacts the efficacy of Polo-like kinase 1 (Plk1) inhibition in tumor cells
Compared to HCT116 p21+/+ cells, HCT116 cells without p21 are more vulnerable to Plk1 inhibition by showing a stronger induction of mitotic arrest (Fig. 2), DNA damage (Fig. 6), apoptosis (Fig. 4) and inhibition of proliferation (Fig. 1)
Summary
The Cdk-interacting protein p21Cip1/CDKN1A (p21) plays key roles in a broad range of cellular events like cell cycle regulation, apoptosis, differentiation, cytoskeletal dynamics, cell migration, gene transcription, DNA repair, reprogramming of induced pluripotent stem cells, aging and onset of senescence [1]. The best studied member, is a key regulator of different cell cycle events and critical for multiple stages of mitosis including mitotic entry, spindle formation, chromosome segregation and cytokinesis [9]. The effect of Plk inhibition is well characterized, it induces mitotic arrest and apoptosis, leading further to a reduced proliferation in vitro and inhibited tumor growth in vivo [10]. Poloxin targets Plk in a panel of cancer cell lines with a high specificity by showing prometaphase arrest, delocalization of Plk itself, reduction of γ‐tubulin recruitment to centrosomes, defects in the mitotic spindle formation, activation of the spindle assembly checkpoint and induction of apoptosis, and it inhibits tumor growth in vivo [18,19,20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
