p53-Mediated Molecular Control of Autophagy in Tumor Cells

Abstract

Autophagy is an indispensable mechanism of the eukaryotic cell, facilitating the removal and renewal of cellular components and thereby balancing the cell’s energy consumption and homeostasis. Deregulation of autophagy is now regarded as one of the characteristic key features contributing to the development of tumors. In recent years, the suppression of autophagy in combination with chemotherapeutic treatment has been approached as a novel therapy in cancer treatment. However, depending on the type of cancer and context, interference with the autophagic machinery can either promote or disrupt tumorigenesis. Therefore, disclosure of the major signaling pathways that regulate autophagy and control tumorigenesis is crucial. To date, several tumor suppressor proteins and oncogenes have emerged as eminent regulators of autophagy whose depletion or mutation favor tumor formation. The mammalian cell “janitor” p53 belongs to one of these tumor suppressors that are most commonly mutated in human tumors. Experimental evidence over the last decade convincingly reports that p53 can act as either an activator or an inhibitor of autophagy depending on its subcellular localization and its mode of action. This finding gains particular significance as p53 deficiency or mutant variants of p53 that accumulate in the cytoplasm of tumor cells enable activation of autophagy. Accordingly, we recently identified p53 as a molecular hub that regulates autophagy and apoptosis in histone deacetylase inhibitor-treated uterine sarcoma cells. In light of this novel experimental evidence, in this review, we focus on p53 signaling as a mediator of the autophagic pathway in tumor cells.

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

“…Despite such complexities, as recently pointed out by White-Gilbertson and Voelkel-Johnson [142], the field of cancer cell dormancy (e.g., through formation of PGCCs) "is at an exciting moment, when bench-to-bedside research has the potential to make a difference in the lives of many cancer patients." For those who are interested in further reading, we suggest seminal/recent papers on reversible cancer cell polyploidy and senescence [87,88,95,99,100,104,118,142,143] that were discussed herein as well as papers on related topics such as therapy-induced autophagy [95,144,145] and genome chaos/micronucleation [146][147][148] that were beyond the scope of the current review.…”

p53-Autophagy-Metastasis Link

“…Importantly, two more p53-inducible signaling molecules, DRAM (damage-regulated autophagy modulator) and p14ARF, are involved in the regulation of the autophagy pathway and are also able to activate apoptosis. Thus, p53 is thought to indirectly facilitate further progression of apoptosis due to the activation of autophagy, especially in cancer cells [ 25 , 26 ] p53 has also been found to repress autophagy to different degrees, depending on the phase of the cell cycle [ 27 ]. Finally, p53 was also shown to increase genomic stability via suppression of retrotransposons, whose overexpression leads to mutagenesis [ 28 ].…”

The Links between Parkinson’s Disease and Cancer

“…Depending on whether the p53 protein is present in the cell nucleus or cytoplasm, it can initiate or inhibit autophagy [ 182 ]. It has also been shown that p53 deficiency or mutated p53 variants that accumulate in the cytoplasm of cancer cells allow the activation of autophagy [ 183 ].…”