Cancer chemoresistance: The relationship between p53 and multidrug transporters

Abstract

Extensive studies indicate that both p53 and multidrug transporters play important roles in chemoresistance. Since the initial reports a decade ago demonstrating a transcriptional dependence of the ABCB1 gene (MDR) promoter by p53, much data have been accumulated. However, despite being the subject of intense study, this p53-MDR relationship remains unclear in human cancers. The data are confounded by variable and contrasting results when considering the in vitro regulation and attempting to draw parallels in tissue specimens. The original model suggested that wild-type p53 downregulates the ABCB1 promoter, whereas mutant p53 increases expression of ABCB1. This review summarizes the data for and against this hypothesis. What emerges from these studies is a complex picture, where data have been obtained in support of this hypothesis, but there are also many circumstances where it is not supported. Taken together, these data suggest that the relationship between p53 and multidrug transporters is conditional. It is dependent on cellular environment, the drug used, and the nature of the p53 mutation.

Coexpression of p53 protein and MDR functional phenotype in leukemias: The predominant association in chronic myeloid leukemia

“…Single or multiple pathways, accounting for drug resistance, can be operative in leukemic cells, depending on drug specificity and genetic alterations arising during the progression of leukemia (11). This is the case of drug resistance related to MRP efflux pump and glutathione (1), while p53 mutations are associated with chemoresistance in several neoplastic conditions in which Pgp and MRP functions are affected (11-13,36 -39).…”

“…Similar to findings provided by p53 detection, the MDR functional phenotype was more often observed in transformed phases of CML, secondary and relapsed AML, and Richter's syndrome of CLL. Pgp and MRP have recently been showed to be activated in association with overexpression of mutant or inactivated p53 protein (11). Coexpression of p53 protein and efflux pumps occurs in solid tumors, representing the strongest prognostic factor for shorter survival in locally advanced breast cancer (49), and is associated with a poor prognosis in osteosarcoma (50).…”

“…The dysfunction of apoptotic pathways, either as an isolated mechanism of drug resistance or in conjunction with overexpression of one or several efflux-pump proteins, might play a relevant role in therapeutic failure. Within this context, the relevance of p53 status on drug resistance is crucial and has been under intense investigation (11).…”

“…In 1992, Chin et al (12) reported that mutant p53 stimulated mdr-1 promoter activity and, more recently, other reports suggested that MRP is affected by p53 mutations (13)(14)(15), because mutant p53 proteins upregulated Pgp and MRP expression, while wild-type p53 downregulated expression of multidrug-resistant proteins (11,16,17). p53 is a transcription factor involved in cell cycle arrest and induction of apoptosis in genetically damaged cells, although the wild-type p53 protein, normally present in the cell nucleus, can not be detected in the majority of normal cells due to its short half-life (18).…”

Anthracyclines induce the accumulation of mutant p53 through E2F1-dependent and -independent mechanisms

“…It is conceivable that this treatment, if not successful in killing a tumor cell, may instead promote the mutant p53-associated gain of function. As a consequence, the cells may become more resistant to further cycles of genotoxic therapy (Blandino et al, 1999;Bush and Li, 2002). Mutant p53 gain of function would also include cell spread, invasion and metastasis (Heinlein et al, 2008;Adorno et al, 2009;Muller et al, 2009;Wang et al, 2009).…”