scholarly journals Oncogenic Alternative Splicing Switches: Role in Cancer Progression and Prospects for Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Serena Bonomi ◽  
Stefania Gallo ◽  
Morena Catillo ◽  
Daniela Pignataro ◽  
Giuseppe Biamonti ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Progression ◽  
Cancer Treatments ◽  
Splicing Regulators ◽  
Transcriptional Regulatory Mechanism ◽  
Transcriptional Regulatory ◽  
Anti Cancer ◽  
Alternatively Spliced ◽  
Splicing Isoforms

Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.

scholarly journals Contrast effects of autophagy in the treatment of bladder cancer

2020 ◽  
pp. 153537022095933
Author(s):  
Ece Konac ◽  
Yener Kurman ◽  
Sümer Baltaci
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Treatment Options ◽  
Treatment Resistance ◽  
Therapy Resistance ◽  
Dual Role ◽  
Cancer Treatments ◽  
Chemotherapy Drugs ◽  
Anti Cancer

Bladder cancer is a disease that negatively affects patients’ quality of life, but treatment options have remained unchanged for a long time. Although promising results have been achieved with current bladder cancer treatments, cancer recurrence, progression, and therapy resistance are the most severe problems preventing the efficiency of bladder cancer treatments. Autophagy refers to an evolutionarily conserved catabolic process in which proteins, damaged organelles, and cytoplasmic components are degraded by lysosomal enzymes. Autophagy regulates the therapeutic response to the chemotherapy drugs, thus determining the effect of therapy on cancer cells. Autophagy is a stress-induced cell survival mechanism and its excessive stimulation can cause resistance of tumor cells to therapeutic agents. Depending on the conditions, an increase in autophagy may cause treatment resistance or autophagic cell death, and it is related to important anti-cancer mechanisms, such as apoptosis. Therefore, understanding the roles of autophagy under different conditions is important for designing effective anti-cancer agents. The dual role of autophagy in cancer has attracted considerable attention in respect of bladder cancer treatment. In this review, we summarize the basic characteristics of autophagy, including its mechanisms, regulation, and functions, and we present examples from current studies concerning the dual role of autophagy in bladder cancer progression and therapy. Impact statement Autophagy acts as an intracellular recycling system. Infection and mitochondrial damage, maintaining cellular homeostasis, orchestrating nutrient stress, hypoxia, and oxidative stress are some of the physiological roles associated with autophagy. Autophagy has also context-dependent roles in cancer. Autophagy has a significant impact on tumor initiation and promotion, with both tumor-suppressive and tumor-promoting roles. Unfortunately, conventional systemic chemotherapy for cancer therapy has been reported to have primary limitations such as chemo-resistance of targeted cells. The cytoprotective role of autophagy has been postulated as one of the causes of this resistance. Hence, combination therapy using autophagy inhibitors has recently started to emerge as a noteworthy strategy in the treatment of cancer. Therefore, targeting the autophagy pathways may be a potential therapeutic strategy for addressing cancer progression or therapy resistance in the near future. This review will provide a novel insight to understanding the paradoxical roles of autophagy in tumor suppression and tumor promotion.

scholarly journals Splicing-associated chromatin signatures: a combinatorial and position-dependent role for histone marks in splicing definition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
E. Agirre ◽  
A. J. Oldfield ◽  
N. Bellora ◽  
A. Segelle ◽  
R. F. Luco
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Embryonic Stem ◽  
Chromatin Modifications ◽  
Histone Marks ◽  
Splicing Regulators ◽  
Machine Learning Approach ◽  
Alternatively Spliced ◽  
Rna Motif ◽  
Regulation Changes

AbstractAlternative splicing relies on the combinatorial recruitment of splicing regulators to specific RNA binding sites. Chromatin has been shown to impact this recruitment. However, a limited number of histone marks have been studied at a global level. In this work, a machine learning approach, applied to extensive epigenomics datasets in human H1 embryonic stem cells and IMR90 foetal fibroblasts, has identified eleven chromatin modifications that differentially mark alternatively spliced exons depending on the level of exon inclusion. These marks act in a combinatorial and position-dependent way, creating characteristic splicing-associated chromatin signatures (SACS). In support of a functional role for SACS in coordinating splicing regulation, changes in the alternative splicing of SACS-marked exons between ten different cell lines correlate with changes in SACS enrichment levels and recruitment of the splicing regulators predicted by RNA motif search analysis. We propose the dynamic nature of chromatin modifications as a mechanism to rapidly fine-tune alternative splicing when necessary.

Role of protein S-Glutathionylation in cancer progression and development of resistance to anti-cancer drugs

2021 ◽  
Vol 704 ◽  
pp. 108890
Author(s):  
Debojyoti Pal ◽  
Archita Rai ◽  
Rahul Checker ◽  
R.S. Patwardhan ◽  
Babita Singh ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Protein S ◽  
Cancer Drugs ◽  
Development Of Resistance ◽  
Anti Cancer

scholarly journals Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy

2018 ◽  
Vol 19 (12) ◽  
pp. 3950 ◽  
Author(s):  
Marilina García-Aranda ◽  
Elisabet Pérez-Ruiz ◽  
Maximino Redondo
Keyword(s):  
Cancer Treatment ◽  
World Health ◽  
Apoptosis Resistance ◽  
Hallmarks Of Cancer ◽  
Cancer Treatments ◽  
Over Expression ◽  
Promising Strategy ◽  
Anti Cancer ◽  
Health Organization

Abstract: According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. The identification of novel targets for cancer treatment is an area of intense work that has led Bcl-2 over-expression to be proposed as one of the hallmarks of cancer and Bcl-2 inhibition as a promising strategy for cancer treatment. In this review, we describe the different pathways related to programmed cell death, the role of Bcl-2 family members in apoptosis resistance to anti-cancer treatments, and the potential utility of Bcl-2 inhibitors to overcome resistance to chemo- and immunotherapy.

scholarly journals MBNL1 alternative splicing isoforms play opposing roles in cancer

2018 ◽  
Vol 1 (5) ◽  
pp. e201800157 ◽  
Author(s):  
Tommaso Tabaglio ◽  
Diana HP Low ◽  
Winnie Koon Lay Teo ◽  
Pierre Alexis Goy ◽  
Piotr Cywoniuk ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Gene Function ◽  
Dominant Negative ◽  
Individual Gene ◽  
Cancer Types ◽  
Splicing Isoforms ◽  
Isoform Switching ◽  
And Migration

The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Δex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Δex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.

scholarly journals Alternative Splicing of Transcription Factors' Genes: Beyond the Increase of Proteome Diversity

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
David Talavera ◽  
Modesto Orozco ◽  
Xavier de la Cruz
Keyword(s):  
Transcription Factors ◽  
Alternative Splicing ◽  
Expression Patterns ◽  
Developmental Changes ◽  
Functional Families ◽  
Transcription Regulators ◽  
Alternatively Spliced ◽  
The Impact ◽  
Human And Mouse

Functional modification of transcription regulators may lead to developmental changes and phenotypical differences between species. In this work, we study the influence of alternative splicing on transcription factors in human and mouse. Our results show that the impact of alternative splicing on transcription factors is similar in both species, meaning that the ways to increase variability should also be similar. However, when looking at the expression patterns of transcription factors, we observe that they tend to diverge regardless of the role of alternative splicing. Finally, we hypothesise that transcription regulation of alternatively spliced transcription factors could play an important role in the phenotypical differences between species, without discarding other phenomena or functional families.

Crosstalk between cancer and haemostasis

2012 ◽  
Vol 32 (02) ◽  
pp. 95-104 ◽  
Author(s):  
C. Bokemeyer ◽  
F. Langer
Keyword(s):  
Cancer Progression ◽  
Tumour Progression ◽  
Modern Concept ◽  
Anti Cancer ◽  
Haematogenous Metastasis ◽  
Triangular Network ◽  
Cell Dissemination ◽  
Patient Subgroups ◽  
Tumour Cell Dissemination

SummaryCancer is characterized by bidirectional interrelations between tumour progression, coagulation activation, and inflammation. Tissue factor (TF), the principal initiator of the coagulation protease cascade, is centrally positioned in this complex triangular network due to its pleiotropic effects in haemostasis, angiogenesis, and haematogenous metastasis. While formation of macroscopic thrombi is the correlate of cancer-associated venous thromboembolism (VTE), a major healthcare burden in clinical haematology and oncology, microvascular thrombosis appears to be critically important to blood-borne tumour cell dissemination. In this regard, expression of TF in malignant tissues as well as shedding of TFbearing microparticles into the circulation are thought to be regulated by defined genetic events relevant to pathological cancer progression, thus directly linking Trousseau’s syndrome to molecular tumourigenesis.Because pharmacological inhibition of the TF pathway in selective tumour types and patient subgroups would be in line with the modern concept of individualized, targeted anti-cancer therapy, this review will focus on the role of TF in tumour biology and cancer-associated VTE.

The role of microvesicles in cancer progression and drug resistance

2013 ◽  
Vol 41 (1) ◽  
pp. 293-298 ◽  
Author(s):  
Samireh Jorfi ◽  
Jameel M. Inal
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cancer Progression ◽  
Chemotherapeutic Agents ◽  
Malignant Cells ◽  
Intercellular Transport ◽  
Wide Range ◽  
Anti Cancer ◽  
Mdr Multidrug Resistance

Microvesicles are shed constitutively, or upon activation, from both normal and malignant cells. The process is dependent on an increase in cytosolic Ca2+, which activates different enzymes, resulting in depolymerization of the actin cytoskeleton and release of the vesicles. Drug resistance can be defined as the ability of cancer cells to survive exposure to a wide range of anti-cancer drugs, and anti-tumour chemotherapeutic treatments are often impaired by innate or acquired MDR (multidrug resistance). Microvesicles released upon chemotherapeutic agents prevent the drugs from reaching their targets and also mediate intercellular transport of MDR proteins.

scholarly journals Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)

2020 ◽  
Vol 13 (2) ◽  
pp. 20
Author(s):  
Quentin Spillier ◽  
Séverine Ravez ◽  
Judith Unterlass ◽  
Cyril Corbet ◽  
Charline Degavre ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Structure Activity Relationship ◽  
Therapeutic Agents ◽  
Activity Relationship ◽  
Cancer Treatments ◽  
Promising Strategy ◽  
Structure Activity ◽  
Phosphoglycerate Dehydrogenase ◽  
Relationship Study

For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH.

scholarly journals N-cadherin antagonists as oncology therapeutics

2015 ◽  
Vol 370 (1661) ◽  
pp. 20140039 ◽  
Author(s):  
Orest W. Blaschuk
Keyword(s):  
Cell Adhesion ◽  
Cancer Progression ◽  
Structural Integrity ◽  
Cancer Therapies ◽  
Transmembrane Glycoprotein ◽  
Anti Cancer ◽  
Different Types ◽  
Poorly Differentiated ◽  
Novel Strategy

The cell adhesion molecule (CAM), N-cadherin, has emerged as an important oncology therapeutic target. N-cadherin is a transmembrane glycoprotein mediating the formation and structural integrity of blood vessels. Its expression has also been documented in numerous types of poorly differentiated tumours. This CAM is involved in regulating the proliferation, survival, invasiveness and metastasis of cancer cells. Disruption of N-cadherin homophilic intercellular interactions using peptide or small molecule antagonists is a promising novel strategy for anti-cancer therapies. This review discusses: the discovery of N-cadherin, the mechanism by which N-cadherin promotes cell adhesion, the role of N-cadherin in blood vessel formation and maintenance, participation of N-cadherin in cancer progression, the different types of N-cadherin antagonists and the use of N-cadherin antagonists as anti-cancer drugs.

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