scholarly journals Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 361 ◽  
Author(s):  
Marco Cordani ◽  
Giovanna Butera ◽  
Raffaella Pacchiana ◽  
Francesca Masetto ◽  
Nidula Mullappilly ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Antioxidant Activities ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Antioxidant Systems ◽  
Mutant P53 ◽  
Tp53 Tumor Suppressor Gene ◽  
Altered Gene ◽  
P53 Isoforms

The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an “Achilles heel” of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene.

scholarly journals Antitumor Effects of PRIMA-1 and PRIMA-1Met (APR246) in Hematological Malignancies: Still a Mutant P53-Dependent Affair?

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 98
Author(s):  
Paola Menichini ◽  
Paola Monti ◽  
Andrea Speciale ◽  
Giovanna Cutrona ◽  
Serena Matis ◽  
...  
Keyword(s):  
Hematological Malignancies ◽  
Cell Metabolism ◽  
Therapy Response ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Lower Percentage ◽  
Mutant P53 ◽  
Wild Type ◽  
Antitumor Effects ◽  
Tp53 Tumor Suppressor Gene

Because of its role in the regulation of the cell cycle, DNA damage response, apoptosis, DNA repair, cell migration, autophagy, and cell metabolism, the TP53 tumor suppressor gene is a key player for cellular homeostasis. TP53 gene is mutated in more than 50% of human cancers, although its overall dysfunction may be even more frequent. TP53 mutations are detected in a lower percentage of hematological malignancies compared to solid tumors, but their frequency generally increases with disease progression, generating adverse effects such as resistance to chemotherapy. Due to the crucial role of P53 in therapy response, several molecules have been developed to re-establish the wild-type P53 function to mutant P53. PRIMA-1 and its methylated form PRIMA-1Met (also named APR246) are capable of restoring the wild-type conformation to mutant P53 and inducing apoptosis in cancer cells; however, they also possess mutant P53-independent properties. This review presents the activities of PRIMA-1 and PRIMA-1Met/APR246 and describes their potential use in hematological malignancies.

scholarly journals Attenuation of p53 mutant as an approach for treatment Her2-positive cancer

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Olga Fedorova ◽  
Alexandra Daks ◽  
Oleg Shuvalov ◽  
Alena Kizenko ◽  
Alexey Petukhov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Suppressor Gene ◽  
Mutant Form ◽  
Her2 Positive ◽  
Surface Receptors ◽  
Tp53 Tumor Suppressor Gene ◽  
Approved Drugs ◽  
High Degree

Abstract Breast cancer is one of the world’s leading causes of oncological disease-related death. It is characterized by a high degree of heterogeneity on the clinical, morphological, and molecular levels. Based on molecular profiling breast carcinomas are divided into several subtypes depending on the expression of a number of cell surface receptors, e.g., ER, PR, and HER2. The Her2-positive subtype occurs in ~10–15% of all cases of breast cancer, and is characterized by a worse prognosis of patient survival. This is due to a high and early relapse rate, as well as an increased level of metastases. Several FDA-approved drugs for the treatment of Her2-positive tumors have been developed, although eventually cancer cells develop drug resistance. These drugs target either the homo- or heterodimerization of Her2 receptors or the receptors’ RTK activity, both of them being critical for the proliferation of cancer cells. Notably, Her2-positive cancers also frequently harbor mutations in the TP53 tumor suppressor gene, which exacerbates the unfavorable prognosis. In this review, we describe the molecular mechanisms of RTK-specific drugs and discuss new perspectives of combinatorial treatment of Her2-positive cancers through inhibition of the mutant form of p53.

scholarly journals Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies

Blood ◽  
2012 ◽  
Vol 119 (16) ◽  
pp. 3668-3683 ◽  
Author(s):  
Zijun Y. Xu-Monette ◽  
L. Jeffrey Medeiros ◽  
Yong Li ◽  
Robert Z. Orlowski ◽  
Michael Andreeff ◽  
...  
Keyword(s):  
Tp53 Gene ◽  
Suppressor Gene ◽  
Wild Type ◽  
Lymphoid Malignancies ◽  
The Status ◽  
Tp53 Tumor Suppressor Gene ◽  
P53 Activation ◽  
Apoptotic Pathways ◽  
P53 Inactivation ◽  
Tp53 Pathway

AbstractMutations of the TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including lymphomas. Tumor suppression by p53 occurs via both transcription-dependent activities in the nucleus by which p53 regulates transcription of genes involved in cell cycle, DNA repair, apoptosis, signaling, transcription, and metabolism; and transcription-independent activities that induces apoptosis and autophagy in the cytoplasm. In lymphoid malignancies, the frequency of TP53 deletions and mutations is lower than in other types of cancer. Nonetheless, the status of TP53 is an independent prognostic factor in most lymphoma types. Dysfunction of TP53 with wild-type coding sequence can result from deregulated gene expression, stability, and activity of p53. To overcome TP53 pathway inactivation, therapeutic delivery of wild-type p53, activation of mutant p53, inhibition of MDM2-mediated degradation of p53, and activation of p53-dependent and -independent apoptotic pathways have been explored experimentally and in clinical trials. We review the mechanisms of TP53 dysfunction, recent advances implicated in lymphomagenesis, and therapeutic approaches to overcoming p53 inactivation.

scholarly journals Targeting cellular senescence in cancer and aging: roles of p53 and its isoforms

2020 ◽  
Vol 41 (8) ◽  
pp. 1017-1029 ◽  
Author(s):  
Jessica Beck ◽  
Casmir Turnquist ◽  
Izumi Horikawa ◽  
Curtis Harris
Keyword(s):  
Cellular Senescence ◽  
Therapeutic Potential ◽  
P53 Protein ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Cellular Reprogramming ◽  
Protein Isoforms ◽  
Age Related ◽  
Alternative Mrna Splicing ◽  
P53 Isoforms

Abstract Cellular senescence and the associated secretory phenotype (SASP) promote disease in the aged population. Targeting senescent cells by means of removal, modulation of SASP or through cellular reprogramming represents a novel therapeutic avenue for treating cancer- and age-related diseases such as neurodegeneration, pulmonary fibrosis and renal disease. Cellular senescence is partly regulated by the TP53 gene, a critical tumor suppressor gene which encodes 12 or more p53 protein isoforms. This review marks a significant milestone of 40 years of Carcinogenesis publication history and p53 research and 15 years of p53 isoform research. The p53 isoforms are produced through initiation at alternative transcriptional and translational start sites and alternative mRNA splicing. These truncated p53 isoform proteins are endogenously expressed in normal human cells and maintain important functional roles, including modulation of full-length p53-mediated cellular senescence, apoptosis and DNA repair. In this review, we discuss the mechanisms and functions of cellular senescence and SASP in health and disease, the regulation of cellular senescence by p53 isoforms, and the therapeutic potential of targeting cellular senescence to treat cancer- and age-associated diseases.

TP53 Mutations in Canine Brain Tumors

2011 ◽  
Vol 49 (5) ◽  
pp. 796-801 ◽  
Author(s):  
D. York ◽  
R. J. Higgins ◽  
R. A. LeCouteur ◽  
A. N. Wolfe ◽  
R. Grahn ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Human Cancer ◽  
Gene Mutations ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Cancer Mutation ◽  
Canine Brain ◽  
Gene Tp53 ◽  
Altered Gene ◽  
P53 Inactivation

The p53 tumor suppressor gene ( TP53) is the most frequently altered gene in human cancer. Mutation of the gene has been shown to be an important mechanism of p53 pathway inactivation in a variety of human brain tumors, particularly those of astrocytic origin. Genomic DNA from a series of 37 glial and 51 nonglial canine brain tumors was sequenced to determine the frequency of TP53 gene mutations involving exons 3–9. Exonic mutations were found in 3 of 88 tumors (3.4%) and specifically in 1 of 18 astrocytic tumors (5.5%). This is markedly lower than that reported in comparable human tumors, suggesting that alternative mechanisms of p53 inactivation are likely to be present if p53 function contributes significantly to oncogenesis in canine brain tumors.

scholarly journals Modified Gold Nanoparticles to Overcome the Chemoresistance to Gemcitabine in Mutant p53 Cancer Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2067
Author(s):  
Eduardo García-Garrido ◽  
Marco Cordani ◽  
Álvaro Somoza
Keyword(s):  
Gold Nanoparticles ◽  
Cancer Cells ◽  
Electrostatic Interactions ◽  
Human Cancer ◽  
Tp53 Gene ◽  
Therapeutic Strategies ◽  
Mutant P53 ◽  
Layer By Layer ◽  
Missense Mutations ◽  
Efficient Delivery

Mutant p53 proteins result from missense mutations in the TP53 gene, the most mutated in human cancer, and have been described to contribute to cancer initiation and progression. Therapeutic strategies for targeting mutant p53 proteins in cancer cells are limited and have proved unsuitable for clinical application due to problems related to drug delivery and toxicity to healthy tissues. Therefore, the discovery of efficient and safe therapeutic strategies that specifically target mutant p53 remains challenging. In this study, we generated gold nanoparticles (AuNPs) chemically modified with low molecular branched polyethylenimine (bPEI) for the efficient delivery of gapmers targeting p53 mutant protein. The AuNPs formulation consists of a combination of polymeric mixed layer of polyethylene glycol (PEG) and PEI, and layer-by-layer assembly of bPEI through a sensitive linker. These nanoparticles can bind oligonucleotides through electrostatic interactions and release them in the presence of a reducing agent as glutathione. The nanostructures generated here provide a non-toxic and powerful system for the delivery of gapmers in cancer cells, which significantly downregulated mutant p53 proteins and altered molecular markers related to cell growth and apoptosis, thus overcoming chemoresistance to gemcitabine.

scholarly journals p53’s Extended Reach: The Mutant p53 Secretome

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 307 ◽  
Author(s):  
Evangelos Pavlakis ◽  
Thorsten Stiewe
Keyword(s):  
Tumor Cell ◽  
Cancer Cells ◽  
Cell Communication ◽  
Tp53 Gene ◽  
Genetic Alterations ◽  
Dominant Negative ◽  
Mutant P53 ◽  
Matrix Remodeling ◽  
Primary Tumor Site ◽  
Metastatic Colonization

p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous extracellular factors that are either soluble or contained within extracellular vesicles such as exosomes. As part of the cellular secretome, they execute key roles in cell-cell communication and extracellular matrix remodeling. Mutations in the p53-encoding TP53 gene are the most frequent genetic alterations in cancer cells, and therefore, have profound impact on the composition of the tumor cell secretome. In this review, we discuss how the loss or dominant-negative inhibition of wild-type p53 in concert with a gain of neomorphic properties observed for many mutant p53 proteins, shapes a tumor cell secretome that creates a supportive microenvironment at the primary tumor site and primes niches in distant organs for future metastatic colonization.

scholarly journals Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 108
Author(s):  
Jolanda Magri ◽  
Alessandro Gasparetto ◽  
Laura Conti ◽  
Enzo Calautti ◽  
Chiara Cossu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Current Knowledge ◽  
Tp53 Gene ◽  
Metabolic Reprogramming ◽  
Mutant P53 ◽  
Wild Type ◽  
Glutathione Biosynthesis ◽  
Tumor Associated Antigen ◽  
Promising Target ◽  
Cancer Types

The cystine/glutamate antiporter xCT is a tumor-associated antigen that has been newly identified in many cancer types. By participating in glutathione biosynthesis, xCT protects cancer cells from oxidative stress conditions and ferroptosis, and contributes to metabolic reprogramming, thus promoting tumor progression and chemoresistance. Moreover, xCT is overexpressed in cancer stem cells. These features render xCT a promising target for cancer therapy, as has been widely reported in the literature and in our work on its immunotargeting. Interestingly, studies on the TP53 gene have revealed that both wild-type and mutant p53 induce the post-transcriptional down modulation of xCT, contributing to ferroptosis. Moreover, APR-246, a small molecule drug that can restore wild-type p53 function in cancer cells, has been described as an indirect modulator of xCT expression in tumors with mutant p53 accumulation, and is thus a promising drug to use in combination with xCT inhibition. This review summarizes the current knowledge of xCT and its regulation by p53, with a focus on the crosstalk of these two molecules in ferroptosis, and also considers some possible combinatorial strategies that can make use of APR-246 treatment in combination with anti-xCT immunotargeting.

scholarly journals A combination approach of pseudotime analysis and mathematical modeling for understanding drug-resistant mechanisms

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shigeyuki Magi ◽  
Sewon Ki ◽  
Masao Ukai ◽  
Elisa Domínguez-Hüttinger ◽  
Atsuhiko T Naito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Sequential Analysis ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Tamoxifen Resistance ◽  
Equation Model ◽  
Altered Gene

AbstractCancer cells acquire drug resistance through the following stages: nonresistant, pre-resistant, and resistant. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing indicates that tamoxifen-resistant cells can be subgrouped into two, one showing altered gene expression related to metabolic regulation and another showing high expression levels of adhesion-related molecules and histone-modifying enzymes. Pseudotime analysis showed a cell transition trajectory to the two resistant subgroups that stem from a shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted and experimentally validated that inhibition of transition to both resistant subtypes would prevent the appearance of tamoxifen resistance.

scholarly journals A Combination Approach of Pseudotime Analysis And Mathematical Modeling For Understanding The Drug-Resistant Mechanisms

2021 ◽  
Author(s):  
Shigeyuki Magi ◽  
Sewon Ki ◽  
Masao Ukai ◽  
Elisa Domínguez-Hüttinger ◽  
Atsuhiko Naito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Sequential Analysis ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Tamoxifen Resistance ◽  
Equation Model ◽  
Altered Gene

Abstract Cancer cells acquire drug resistance through the following nonresistant, pre-resistant, and resistant stages. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing indicates that tamoxifen-resistant cells can be subgrouped into two, one showing altered gene expression related to metabolic regulation. The other showed high expression levels of adhesion-related molecules and histone-modifying enzymes. Pseudotime analysis showed a cell transition trajectory to the two resistant subgroups that stem from a shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted and experimentally validated that inhibition of transition to both resistant subtypes would prevent the appearance of tamoxifen resistance.

Sign in / Sign up

Export Citation Format

Share Document