P53 mutations in colorectal cancer - molecular pathogenesis and pharmacological reactivation

Abstract

Colorectal cancer (CRC) is one of the most common malignancies with high prevalence and low 5-year survival. CRC is a heterogeneous disease with a complex, genetic and biochemical background. It is now generally accepted that a few important intracellular signaling pathways, including Wnt/β-catenin signaling, Ras signaling, and p53 signaling are frequently dysregulated in CRC. Patients with mutant p53 gene are often resistant to current therapies, conferring poor prognosis. Tumor suppressor p53 protein is a transcription factor inducing cell cycle arrest, senescence, and apoptosis under cellular stress. Emerging evidence from laboratories and clinical trials shows that some small molecule inhibitors exert anti-cancer effect via reactivation and restoration of p53 function. In this review, we summarize the p53 function and characterize its mutations in CRC. The involvement of p53 mutations in pathogenesis of CRC and their clinical impacts will be highlighted. Moreover, we also describe the current achievements of using p53 modulators to reactivate this pathway in CRC, which may have great potential as novel anti-cancer therapy.

Keywords: Colorectal cancer; Gene therapy; PRIMA-1MET; Small molecule inhibitor; Tumor suppressor; p53.

Figure 1

Structure and function of p53 tumor suppressor. A: Schematic of p53 protein structure. The function domains and corresponding amino acid regions are indicated. N-terminus transcription-activation domain (TAD): Residues 1-63; AD1: Residues 1-42 for G1 arrest and apoptotic activity; AD2: Residues 43-63 important for senescence-activity; PD: Residues 64-92 important for apoptotic activity; DBD: Residues 102-292 responsible for binding the p53 co-repressors; NLSD: Residues 316-324, 370-376, 380-386; OD: Residues 325-356; NESD: Residues 340-353; B: In normal cells, p53 activates a plethora of target genes involved in diverse biological processes in response to cellular stress. Ub: Ubiquitin; PD: Poly-proline domain; DBD: DNA binding core domain; OD: Homo-oligomerization domain; NESD: Nuclear export signaling domain; NLSD: Nuclear localization signaling domain.

Figure 2

Schematic representation of miRNAs regulating p53 pathway and subsequent tumorigenesis.

Figure 3

Small molecule compounds pharmacologically reactivating of p53 function. MI43 and Nutlin-3 bound to MDM2 blocking MDM2-p53 interaction. RITA bound to p53 interfering MDM2-p53 interaction. α-Lipoic acid increased p53 protein stability and its apoptotic effect. Quinacrine induced the autophagy-associated cell death in a p53-dependent manner. NSC17632 activated p53-like activatity dependent on p73. PRIMA-1/PRIMA-1^MET restored mutant p53 to exert apoptotic effect. Maslinic acid and Epicatechin gallate as plant extraction modulated the expression of p53 and its target genes in p53-dependent apoptotic and cell cycle arrest pathway.