Targeting p27^Kip1 protein: its relevance in the therapy of human cancer

Abstract

Introduction: Cell division cycle progression is achieved by a sequential and stringently concerted activation of a family of serine–threonine kinases, namely the cyclin-dependent kinases (CDKs). p27^Kip1 is a pivotal CDK inhibitor and a tight modulator of CDK-dependent phenotypes. Thus, p27^Kip1 plays a fundamental role in key cellular processes such as proliferation, differentiation, apoptosis, substrate adhesion and motility. Intriguingly, when p27^Kip1 is localized in the nucleus, it acts as an antiproliferative protein, while, in the cytosol, p27^Kip1 promotes cytoskeleton remodeling and might positively influence metastatization. Downregulation of p27^Kip1 nuclear level or its cytosolic mislocalization are consistently correlated with poor prognosis of numerous types of human epithelial and non-epithelial cancers.

Areas covered: This review illustrates the basic structural features of p27^Kip1 protein, its metabolism and alterations in human malignancies, along with describing anticancer strategies based on targeting p27^Kip1.

Expert opinion: Given the role of p27^Kip1 in the control of cell proliferation and its decreased level observed in malignancies with poor outcome, drugs able to handle the protein levels and localization might represent an important goal for novel specific and effective anticancer strategies. Although no convincing proofs have been reported, putative negative consequences of p27^Kip1 targeting might be also conceivable.

Keywords::

• cancer therapy
• cyclin-dependent kinases
• p27^Kip1
• p27^Kip1 metabolism

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