International Journal of Molecular Sciences

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Dear Colleagues,

The p53 family comprises three transcription factors, p53, p63 and p73, that exhibit diverse biological activities. To understand the functioning of the p53 pathway, all family members should be considered. Their main function in normal cells is the maintenance of genome stability and cell homeostasis. However, their tumour suppressor function is abrogated in the majority of cancer cells due to mutations or altered expression of specific isoforms. p53 family isoforms form homotetramers or heterotetramers and this can change the function of canonical p53 proteins, thus influencing the p53 signalling pathway, causing cancer progression or even resistance to therapy. Accordingly, many p53 family members/isoforms are shown to be the modulators of acquired resistance to targeted cancer therapy. However, the prognostic relevance in the clinics is attributed only to mutant p53. Different strategies have been investigated for targeting p53-dysfunctional cancers using small molecules and several compounds have already reached clinical trials. Therefore, p53 family members/isoforms are potential targets for cancer therapy whose activity can potentially be modulated with the aim to re-establish a functional p53 pathway.

This Special Issue focuses on the role of the p53 family members in cancer therapy, their function as modulators of the therapy response and their potential as predictive or prognostic markers as well as therapeutic targets.

This special issue is supervised by Dr. Ignacija Vlasic and Dr. Neda Slade, and assisted by our Topical Advisory Panel Member Dr. Anđela Horvat (Ruđer Bošković Institute, Croatia).

Dr. Ignacija Vlasic
Dr. Neda Slade
Guest Editors

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Keywords

p53 family of proteins
p53 family isoforms/splice variants
p53 family crosstalk
mutant p53
altered expression of p53 family members/isoforms
cancer progression
targeted therapy
therapy resistance

Published Papers (2 papers)

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Research

24 pages, 4849 KiB

Open AccessArticle

Amyloid Beta Leads to Decreased Acetylcholine Levels and Non-Small Cell Lung Cancer Cell Survival via a Mechanism That Involves p38 Mitogen-Activated Protein Kinase and Protein Kinase C in a p53-Dependent and -Independent Manner

by Hind Al Khashali, Ravel Ray, Ban Darweesh, Caroline Wozniak, Ben Haddad, Stuti Goel, Issah Seidu, Jeneen Khalil, Brooke Lopo, Nayrooz Murshed, Jeffrey Guthrie, Deborah Heyl and Hedeel Guy Evans

Int. J. Mol. Sci. 2024, 25(9), 5033; https://doi.org/10.3390/ijms25095033 - 5 May 2024

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Abstract

Several studies have shown an inverse correlation between the likelihood of developing a neurodegenerative disorder and cancer. We previously reported that the levels of amyloid beta (Aβ), at the center of Alzheimer’s disease pathophysiology, are regulated by acetylcholinesterase (AChE) in non-small cell lung cancer (NSCLC). Here, we examined the effect of Aβ or its fragments on the levels of ACh in A549 (p53 wild-type) and H1299 (p53-null) NSCLC cell media. ACh levels were reduced by cell treatment with Aβ 1–42, Aβ 1–40, Aβ 1–28, and Aβ 25–35. AChE and p53 activities increased upon A549 cell treatment with Aβ, while knockdown of p53 in A549 cells increased ACh levels, decreased AChE activity, and diminished the Aβ effects. Aβ increased the ratio of phospho/total p38 MAPK and decreased the activity of PKC. Inhibiting p38 MAPK reduced the activity of p53 in A549 cells and increased ACh levels in the media of both cell lines, while opposite effects were found upon inhibiting PKC. ACh decreased the activity of p53 in A549 cells, decreased p38 MAPK activity, increased PKC activity, and diminished the effect of Aβ on those activities. Moreover, the negative effect of Aβ on cell viability was diminished by cell co-treatment with ACh. Full article

(This article belongs to the Special Issue Role of p53 Family in Targeted Therapy of Cancers)

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14 pages, 1450 KiB

Open AccessArticle

Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment

by Victoria Neely, Alekhya Manchikalapudi, Khanh Nguyen, Krista Dalton, Bin Hu, Jennifer E. Koblinski, Anthony C. Faber, Sumitra Deb and Hisashi Harada

Int. J. Mol. Sci. 2023, 24(17), 13082; https://doi.org/10.3390/ijms241713082 - 23 Aug 2023

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Abstract

Through a unique genomics and drug screening platform with ~800 solid tumor cell lines, we have found a subset of SCLC cell lines are hypersensitive to venetoclax, an FDA-approved inhibitor of BCL-2. SCLC-A (ASCL1 positive) and SCLC-P (POU2F3 positive), which make up almost 80% of SCLC, frequently express high levels of BCL-2. We found that a subset of SCLC-A and SCLC-P showed high BCL-2 expression but were venetoclax-resistant. In addition, most of these SCLC cell lines have TP53 missense mutations, which make a single amino acid change. These mutants not only lose wild-type (WT) p53 tumor suppressor functions, but also acquire novel cancer-promoting activities (oncogenic, gain-of-function). A recent study with oncogenic mutant (Onc)-p53 knock-in mouse models of SCLC suggests gain-of-function activity can attenuate chemotherapeutic efficacy. Based on these observations, we hypothesize that Onc-p53 confers venetoclax resistance and that simultaneous inhibition of BCL-2 and Onc-p53 induces synergistic anticancer activity in a subset of SCLC-A and SCLC-P. We show here that (1) down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells; (2) targeting Onc-p53 by the HSP90 inhibitor, ganetespib, increases BIM expression and sensitizes to venetoclax in SCLC-P and SCLC-A cells. Although there are currently many combination studies for venetoclax proposed, the concept of simultaneous targeting of BCL-2 and Onc-p53 by the combination of venetoclax and HSP90 inhibitors would be a promising approach for SCLC treatment. Full article

(This article belongs to the Special Issue Role of p53 Family in Targeted Therapy of Cancers)

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