Targeting the p53 signaling pathway in cancer therapy – the promises, challenges and perils

Abstract

Introduction Research over the past three decades has identified p53 as a multifunctional transcription factor, which regulates the expression of >2,500 target genes. p53 impacts myriad, highly diverse cellular processes, including the maintenance of genomic stability and fidelity, metabolism, longevity, and represents one of the most important and extensively studied tumor suppressors. Activated by various stresses, foremost genotoxic damage, hypoxia, heat shock and oncogenic assault, p53 blocks cancer progression by provoking transient or permanent growth arrest, by enabling DNA repair or by advancing cellular death programs. This potent and versatile anti-cancer activity profile, together with genomic and mutational analyses documenting inactivation of p53 in more than 50% of human cancers, motivated drug development efforts to (re-) activate p53 in established tumors. Areas covered In this review the complexities of p53 signaling in cancer are summarized. Current strategies and challenges to restore p53’s tumor suppressive function in established tumors, i.e. adenoviral gene transfer and small molecules to activate p53, to inactivate p53 inhibitors and to restore wild type function of p53 mutant proteins are discussed. Expert opinion It is indubitable that p53 represents an attractive target for the development of anti-cancer therapies. Whether p53 is ‘druggable’, however, remains an area of active research and discussion, as p53 has pro-survival functions and chronic p53 activation accelerates aging, which may compromise the long-term homeostasis of an organism. Thus, the complex biology and dual functions of p53 in cancer prevention and age-related cellular responses pose significant challenges on the development of p53-targeting cancer therapies.

Identification of hub genes and pathways associated with bladder cancer based on co-expression network analysis

“…The p53 signaling pathway had been suggested as a cellular surveillance mechanism for cancer prevention (47). Furthermore, drug development programs are underway to target the p53 signaling pathway (48).…”

p53 is an independent prognostic factor in operable esophageal squamous cell carcinoma: a large-scale study with a long follow-up

“…This protein has been proven to play an important role in the development of EC [25] and represents an attractive target for the development of anti-cancer therapies [26]. Moreover, polymorphisms have been associated with the risk of ESCC [27].…”

Crosstalk between Wnt/β-catenin and Hedgehog/Gli signaling pathways in colon cancer and implications for therapy

“…Restoring p53 function have been developed as a novel therapeutic approaches. 62 In colon cancer, adenovirus mediated p53 gene transfer could induce apoptosis and inhibit growth and angiogenesis. 63 In addition, overexpression of Sufu, PTEN or Gli3R has shown anti-tumor effects on colon cancer cells.…”