Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy

Abstract

Cancer is a leading cause of death worldwide. Targeted therapies aimed at key oncogenic driver mutations in combination with chemotherapy and radiotherapy as well as immunotherapy have benefited cancer patients considerably. Tumor protein p53 (TP53), a crucial tumor suppressor gene encoding p53, regulates numerous downstream genes and cellular phenotypes in response to various stressors. The affected genes are involved in diverse processes, including cell cycle arrest, DNA repair, cellular senescence, metabolic homeostasis, apoptosis, and autophagy. However, accumulating recent studies have continued to reveal novel and unexpected functions of p53 in governing the fate of tumors, for example, functions in ferroptosis, immunity, the tumor microenvironment and microbiome metabolism. Among the possibilities, the evolutionary plasticity of p53 is the most controversial, partially due to the dizzying array of biological functions that have been attributed to different regulatory mechanisms of p53 signaling. Nearly 40 years after its discovery, this key tumor suppressor remains somewhat enigmatic. The intricate and diverse functions of p53 in regulating cell fate during cancer treatment are only the tip of the iceberg with respect to its equally complicated structural biology, which has been painstakingly revealed. Additionally, TP53 mutation is one of the most significant genetic alterations in cancer, contributing to rapid cancer cell growth and tumor progression. Here, we summarized recent advances that implicate altered p53 in modulating the response to various cancer therapies, including chemotherapy, radiotherapy, and immunotherapy. Furthermore, we also discussed potential strategies for targeting p53 as a therapeutic option for cancer.

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

“…The dysregulation of tumor suppressor proteins involved in the control of cell proliferation, migration, invasion, and drug response has been established as a key event in cancer origin and progression to aggressive stages. These largely include p53, p21, pRB, p16, p19, PTEN, Keap1, NRF2, PARP1, Her2, and CDKs that have emerged as therapeutic targets in various types of cancers [ 1 , 2 , 3 , 4 ]. Driven by the functional inactivation of a large number of tumor suppressor genes and activation of oncogenes, it involves a complex network of multiple signaling cascades including replication and cell cycle progression, stress and DNA damage response, cell migration, and EMT that are also modulated by intrinsic and extrinsic stresses [ 5 , 6 ].…”