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24 pages, 11165 KiB

Open AccessArticle

by Aleš Holoubek, Dita Strachotová, Petra Otevřelová, Pavla Röselová, Petr Heřman and Barbora Brodská

Cancers 2021, 13(13), 3266; https://doi.org/10.3390/cancers13133266 - 29 Jun 2021

Cited by 7 | Viewed by 3157

Abstract

Nucleophosmin (NPM) interaction with tumor suppressor p53 is a part of a complex interaction network and considerably affects cellular stress response. The impact of NPM1 mutations on its interaction with p53 has not been investigated yet, although consequences of NPMmut-induced p53 export to [...] Read more.

Nucleophosmin (NPM) interaction with tumor suppressor p53 is a part of a complex interaction network and considerably affects cellular stress response. The impact of NPM1 mutations on its interaction with p53 has not been investigated yet, although consequences of NPMmut-induced p53 export to the cytoplasm are important for understanding the oncogenic potential of these mutations. We investigated p53-NPM interaction in live HEK-293T cells by FLIM-FRET and in cell lysates by immunoprecipitation. eGFP lifetime-photoconversion was used to follow redistribution dynamics of NPMmut and p53 in Selinexor-treated cells. We confirmed the p53-NPMwt interaction in intact cells and newly documented that this interaction is not compromised by the NPM mutation causing displacement of p53 to the cytoplasm. Moreover, the interaction was not abolished for non-oligomerizing NPM variants with truncated oligomerization domain, suggesting that oligomerization is not essential for interaction of NPM forms with p53. Inhibition of the nuclear exporter XPO1 by Selinexor caused expected nuclear relocalization of both NPMmut and p53. However, significantly different return rates of these proteins indicate nontrivial mechanism of p53 and NPMmut cellular trafficking. The altered p53 regulation in cells expressing NPMmut offers improved understanding to help investigational strategies targeting these mutations. Full article

(This article belongs to the Special Issue Tumor Suppressor Genes: Insight into the Cancer Therapy)

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23 pages, 3469 KiB

Open AccessArticle

Insight into Codon Utilization Pattern of Tumor Suppressor Gene EPB41L3 from Different Mammalian Species Indicates Dominant Role of Selection Force

by Utsang Kumar, Rekha Khandia, Shailja Singhal, Nidhi Puranik, Meghna Tripathi, Atul Kumar Pateriya, Raju Khan, Talha Bin Emran, Kuldeep Dhama, Ashok Munjal, Taha Alqahtani and Ali M. Alqahtani

Cancers 2021, 13(11), 2739; https://doi.org/10.3390/cancers13112739 - 1 Jun 2021

Cited by 20 | Viewed by 4198

Abstract

Uneven codon usage within genes as well as among genomes is a usual phenomenon across organisms. It plays a significant role in the translational efficiency and evolution of a particular gene. EPB41L3 is a tumor suppressor protein-coding gene, and in the present study, [...] Read more.

Uneven codon usage within genes as well as among genomes is a usual phenomenon across organisms. It plays a significant role in the translational efficiency and evolution of a particular gene. EPB41L3 is a tumor suppressor protein-coding gene, and in the present study, the pattern of codon usage was envisaged. The full-length sequences of the EPB41L3 gene for the human, brown rat, domesticated cattle, and Sumatran orangutan available at the NCBI were retrieved and utilized to analyze CUB patterns across the selected mammalian species. Compositional properties, dinucleotide abundance, and parity analysis showed the dominance of A and G whilst RSCU analysis indicated the dominance of G/C-ending codons. The neutrality plot plotted between GC12 and GC3 to determine the variation between the mutation pressure and natural selection indicated the dominance of selection pressure (R = 0.926; p < 0.00001) over the three codon positions across the gene. The result is in concordance with the codon adaptation index analysis and the ENc-GC3 plot analysis, as well as the translational selection index (P2). Overall selection pressure is the dominant pressure acting during the evolution of the EPB41L3 gene. Full article

(This article belongs to the Special Issue Tumor Suppressor Genes: Insight into the Cancer Therapy)

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Review

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19 pages, 910 KiB

Open AccessReview

Anti-Cancer Role and Therapeutic Potential of Extracellular Vesicles

by Naoomi Tominaga

Cancers 2021, 13(24), 6303; https://doi.org/10.3390/cancers13246303 - 15 Dec 2021

Cited by 6 | Viewed by 3727

Abstract

Cell–cell communication is an important mechanism in biological processes. Extracellular vesicles (EVs), also referred to as exosomes, microvesicles, and prostasomes, are microvesicles secreted by a variety of cells. EVs are nanometer-scale vesicles composed of a lipid bilayer and contain biological functional molecules, such [...] Read more.

Cell–cell communication is an important mechanism in biological processes. Extracellular vesicles (EVs), also referred to as exosomes, microvesicles, and prostasomes, are microvesicles secreted by a variety of cells. EVs are nanometer-scale vesicles composed of a lipid bilayer and contain biological functional molecules, such as microRNAs (miRNAs), mRNAs, and proteins. In this review, “EVs” is used as a comprehensive term for vesicles that are secreted from cells. EV research has been developing over the last four decades. Many studies have suggested that EVs play a crucial role in cell–cell communication. Importantly, EVs contribute to cancer malignancy mechanisms such as carcinogenesis, proliferation, angiogenesis, metastasis, and escape from the immune system. EVs derived from cancer cells and their microenvironments are diverse, change in nature depending on the condition. As EVs are thought to be secreted into body fluids, they have the potential to serve as diagnostic markers for liquid biopsy. In addition, cells can encapsulate functional molecules in EVs. Hence, the characteristics of EVs make them suitable for use in drug delivery systems and novel cancer treatments. In this review, the potential of EVs as anti-cancer therapeutics is discussed. Full article

(This article belongs to the Special Issue Tumor Suppressor Genes: Insight into the Cancer Therapy)

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53 pages, 25590 KiB

Open AccessReview

A New Story of the Three Magi: Scaffolding Proteins and lncRNA Suppressors of Cancer

by Larissa Kotelevets and Eric Chastre

Cancers 2021, 13(17), 4264; https://doi.org/10.3390/cancers13174264 - 24 Aug 2021

Cited by 9 | Viewed by 4057

Abstract

Scaffolding molecules exert a critical role in orchestrating cellular response through the spatiotemporal assembly of effector proteins as signalosomes. By increasing the efficiency and selectivity of intracellular signaling, these molecules can exert (anti/pro)oncogenic activities. As an archetype of scaffolding proteins with tumor suppressor [...] Read more.

Scaffolding molecules exert a critical role in orchestrating cellular response through the spatiotemporal assembly of effector proteins as signalosomes. By increasing the efficiency and selectivity of intracellular signaling, these molecules can exert (anti/pro)oncogenic activities. As an archetype of scaffolding proteins with tumor suppressor property, the present review focuses on MAGI1, 2, and 3 (membrane-associated guanylate kinase inverted), a subgroup of the MAGUK protein family, that mediate networks involving receptors, junctional complexes, signaling molecules, and the cytoskeleton. MAGI1, 2, and 3 are comprised of 6 PDZ domains, 2 WW domains, and 1 GUK domain. These 9 protein binding modules allow selective interactions with a wide range of effectors, including the PTEN tumor suppressor, the β-catenin and YAP1 proto-oncogenes, and the regulation of the PI3K/AKT, the Wnt, and the Hippo signaling pathways. The frequent downmodulation of MAGIs in various human malignancies makes these scaffolding molecules and their ligands putative therapeutic targets. Interestingly, MAGI1 and MAGI2 genetic loci generate a series of long non-coding RNAs that act as a tumor promoter or suppressor in a tissue-dependent manner, by selectively sponging some miRNAs or by regulating epigenetic processes. Here, we discuss the different paths followed by the three MAGIs to control carcinogenesis. Full article

(This article belongs to the Special Issue Tumor Suppressor Genes: Insight into the Cancer Therapy)

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32 pages, 1859 KiB

Open AccessReview

Therapeutic Strategies Targeting Tumor Suppressor Genes in Pancreatic Cancer

by Kung-Kai Kuo, Pi-Jung Hsiao, Wen-Tsan Chang, Shih-Chang Chuang, Ya-Han Yang, Kenly Wuputra, Chia-Chen Ku, Jia-Bin Pan, Chia-Pei Li, Kohsuke Kato, Chung-Jung Liu, Deng-Chyang Wu and Kazunari K. Yokoyama

Cancers 2021, 13(15), 3920; https://doi.org/10.3390/cancers13153920 - 3 Aug 2021

Cited by 10 | Viewed by 4793

Abstract

The high mortality of pancreatic cancer is attributed to the insidious progression of this disease, which results in a delayed diagnosis and advanced disease stage at diagnosis. More than 35% of patients with pancreatic cancer are in stage III, whereas 50% are in [...] Read more.

The high mortality of pancreatic cancer is attributed to the insidious progression of this disease, which results in a delayed diagnosis and advanced disease stage at diagnosis. More than 35% of patients with pancreatic cancer are in stage III, whereas 50% are in stage IV at diagnosis. Thus, understanding the aggressive features of pancreatic cancer will contribute to the resolution of problems, such as its early recurrence, metastasis, and resistance to chemotherapy and radiotherapy. Therefore, new therapeutic strategies targeting tumor suppressor gene products may help prevent the progression of pancreatic cancer. In this review, we discuss several recent clinical trials of pancreatic cancer and recent studies reporting safe and effective treatment modalities for patients with advanced pancreatic cancer. Full article

(This article belongs to the Special Issue Tumor Suppressor Genes: Insight into the Cancer Therapy)

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20 pages, 2689 KiB

Open AccessReview

Rely on Each Other: DNA Binding Cooperativity Shapes p53 Functions in Tumor Suppression and Cancer Therapy

by Oleg Timofeev and Thorsten Stiewe

Cancers 2021, 13(10), 2422; https://doi.org/10.3390/cancers13102422 - 17 May 2021

Cited by 6 | Viewed by 3985

Abstract

p53 is a tumor suppressor that is mutated in half of all cancers. The high clinical relevance has made p53 a model transcription factor for delineating general mechanisms of transcriptional regulation. p53 forms tetramers that bind DNA in a highly cooperative manner. The [...] Read more.

p53 is a tumor suppressor that is mutated in half of all cancers. The high clinical relevance has made p53 a model transcription factor for delineating general mechanisms of transcriptional regulation. p53 forms tetramers that bind DNA in a highly cooperative manner. The DNA binding cooperativity of p53 has been studied by structural and molecular biologists as well as clinical oncologists. These experiments have revealed the structural basis for cooperative DNA binding and its impact on sequence specificity and target gene spectrum. Cooperativity was found to be critical for the control of p53-mediated cell fate decisions and tumor suppression. Importantly, an estimated number of 34,000 cancer patients per year world-wide have mutations of the amino acids mediating cooperativity, and knock-in mouse models have confirmed such mutations to be tumorigenic. While p53 cancer mutations are classically subdivided into “contact” and “structural” mutations, “cooperativity” mutations form a mechanistically distinct third class that affect the quaternary structure but leave DNA contacting residues and the three-dimensional folding of the DNA-binding domain intact. In this review we discuss the concept of DNA binding cooperativity and highlight the unique nature of cooperativity mutations and their clinical implications for cancer therapy. Full article

(This article belongs to the Special Issue Tumor Suppressor Genes: Insight into the Cancer Therapy)

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26 pages, 4860 KiB

Open AccessReview

The Role of PPARγ Ligands in Breast Cancer: From Basic Research to Clinical Studies

by Giuseppina Augimeri, Cinzia Giordano, Luca Gelsomino, Pierluigi Plastina, Ines Barone, Stefania Catalano, Sebastiano Andò and Daniela Bonofiglio

Cancers 2020, 12(9), 2623; https://doi.org/10.3390/cancers12092623 - 14 Sep 2020

Cited by 41 | Viewed by 5792

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ), belonging to the nuclear receptor superfamily, is a ligand-dependent transcription factor involved in a variety of pathophysiological conditions such as inflammation, metabolic disorders, cardiovascular disease, and cancers. In this latter context, PPARγ is expressed in many tumors including [...] Read more.

Peroxisome proliferator-activated receptor gamma (PPARγ), belonging to the nuclear receptor superfamily, is a ligand-dependent transcription factor involved in a variety of pathophysiological conditions such as inflammation, metabolic disorders, cardiovascular disease, and cancers. In this latter context, PPARγ is expressed in many tumors including breast cancer, and its function upon binding of ligands has been linked to the tumor development, progression, and metastasis. Over the last decade, much research has focused on the potential of natural agonists for PPARγ including fatty acids and prostanoids that act as weak ligands compared to the strong and synthetic PPARγ agonists such as thiazolidinedione drugs. Both natural and synthetic compounds have been implicated in the negative regulation of breast cancer growth and progression. The aim of the present review is to summarize the role of PPARγ activation in breast cancer focusing on the underlying cellular and molecular mechanisms involved in the regulation of cell proliferation, cell cycle, and cell death, in the modulation of motility and invasion as well as in the cross-talk with other different signaling pathways. Besides, we also provide an overview of the in vivo breast cancer models and clinical studies. The therapeutic effects of natural and synthetic PPARγ ligands, as antineoplastic agents, represent a fascinating and clinically a potential translatable area of research with regards to the battle against cancer. Full article

(This article belongs to the Special Issue Tumor Suppressor Genes: Insight into the Cancer Therapy)

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31 pages, 1635 KiB

Open AccessReview

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

by Ping-Lian Yang, Lu-Xin Liu, En-Min Li and Li-Yan Xu

Cancers 2020, 12(9), 2459; https://doi.org/10.3390/cancers12092459 - 30 Aug 2020

Cited by 31 | Viewed by 4686

Abstract

Chemoradiotherapy is one of the most effective and extensively used strategies for cancer treatment. Signal transducer and activator of transcription 3 (STAT3) regulates vital biological processes, such as cell proliferation and cell growth. It is constitutively activated in various cancers and limits the [...] Read more.

Chemoradiotherapy is one of the most effective and extensively used strategies for cancer treatment. Signal transducer and activator of transcription 3 (STAT3) regulates vital biological processes, such as cell proliferation and cell growth. It is constitutively activated in various cancers and limits the application of chemoradiotherapy. Accumulating evidence suggests that STAT3 regulates resistance to chemotherapy and radiotherapy and thereby impairs therapeutic efficacy by mediating its feedback loop and several target genes. The alternative splicing product STAT3β is often identified as a dominant-negative regulator, but it enhances sensitivity to chemotherapy and offers a new and challenging approach to reverse therapeutic resistance. We focus here on exploring the role of STAT3 in resistance to receptor tyrosine kinase (RTK) inhibitors and radiotherapy, outlining the potential of targeting STAT3 to overcome chemo(radio)resistance for improving clinical outcomes, and evaluating the importance of STAT3β as a potential therapeutic approach to overcomes chemo(radio)resistance. In this review, we discuss some new insights into the effect of STAT3 and its subtype STAT3β on chemoradiotherapy sensitivity, and we explore how these insights influence clinical treatment and drug development for cancer. Full article

(This article belongs to the Special Issue Tumor Suppressor Genes: Insight into the Cancer Therapy)

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