Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy.
OBJECTIVE
To review mechanisms underlying mutant p53 (mutp53) gain of function (GOF) and mutp53-induced chemoresistance, and to investigate the role of mutp53 in response to clinical chemotherapy.


METHODS
We searched the PubMed database for clinical studies from the past decade, including data evaluating the impact of mutp53 in clinical chemotherapy response.


RESULTS
Interactions between mutp53 and transcriptional factors, proteins or DNA structures, as well as epigenetic regulation, contribute to mutp53 GOF. Major mechanisms of mutp53-induced chemoresistance include enhanced drug efflux and metabolism, promoting survival, inhibiting apoptosis, upregulating DNA repair, suppressing autophagy, elevating microenvironmental resistance and inducing a stem-like phenotype. Clinically, mutp53 predicted resistance to chemotherapy in diffuse large B-cell lymphoma, and esophageal and oropharyngeal cancers, but its impact on chronic lymphocytic leukemia was unclear. In bladder cancer, mutp53 did not predict resistance, whereas in some breast and ovarian cancers, it was associated with sensitivity to certain chemotherapeutic agents.


CONCLUSIONS
mutp53 has an intricate role in the response to clinical chemotherapy and should not be interpreted in isolation. Furthermore, when predicting tumor response to chemotherapy based on the p53 status, the drugs used should also be taken into consideration. These concepts require further investigation.
Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
Chao
C
He
Lun
L
Li
Xuan
X
Guan
Li
L
Xiong
Xiongying
X
Miao
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D003577:Cytochrome P-450 Enzyme System