scholarly journals Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhihui Dou ◽  
Dapeng Zhao ◽  
Xiaohua Chen ◽  
Caipeng Xu ◽  
Xiaodong Jin ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Structural Characteristics ◽  
Therapy Resistance ◽  
Regulatory Elements ◽  
Aberrant Splicing ◽  
Clinical Role ◽  
Splicing Isoforms ◽  
The Impact ◽  
Splicing Patterns

AbstractBcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

scholarly journals Tumor evolution selectively inactivates the core microRNA machinery for immune evasion

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tian-Yu Song ◽  
Min Long ◽  
Hai-Xin Zhao ◽  
Miao-Wen Zou ◽  
Hong-Jie Fan ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Immune Evasion ◽  
Human Cancer ◽  
Mirna Biogenesis ◽  
Cytokine Signaling ◽  
Tumor Evolution ◽  
Mouse Tumor ◽  
The Core ◽  
The Impact

AbstractCancer cells acquire genetic heterogeneity to escape from immune surveillance during tumor evolution, but a systematic approach to distinguish driver from passenger mutations is lacking. Here we investigate the impact of different immune pressure on tumor clonal dynamics and immune evasion mechanism, by combining massive parallel sequencing of immune edited tumors and CRISPR library screens in syngeneic mouse tumor model and co-culture system. We find that the core microRNA (miRNA) biogenesis and targeting machinery maintains the sensitivity of cancer cells to PD-1-independent T cell-mediated cytotoxicity. Genetic inactivation of the machinery or re-introduction of ANKRD52 frequent patient mutations dampens the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells, largely by abolishing miR-155-targeted silencing of suppressor of cytokine signaling 1 (SOCS1). Expression of each miRNA machinery component strongly correlates with intratumoral T cell infiltration in nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway can be exploited by cancer cells to escape from T cell-mediated elimination and immunotherapy.

scholarly journals Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance

2019 ◽  
Vol 21 (1) ◽  
pp. 237 ◽  
Author(s):  
Husain Yar Khan ◽  
James Ge ◽  
Misako Nagasaka ◽  
Amro Aboukameel ◽  
Gabriel Mpilla ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Rho Gtpase ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Anaplastic Thyroid Cancer ◽  
Therapy Resistance ◽  
Molecular Profile ◽  
The Impact ◽  
Thyroid Cancer Cells

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.

scholarly journals Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Okay Saydam ◽  
Nurten Saydam
Keyword(s):  
Host Cell ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Metastasis ◽  
Human Cancer ◽  
Therapy Resistance ◽  
Host Cells ◽  
Human Cancer Cells ◽  
Parasitic Lifestyle

Cancer metastasis is the major cause of death from cancer (Massague and Obenauf, 2016; Steeg, 2016). The extensive genetic heterogeneity and cellular plasticity of metastatic tumors set a prime barrier for the current cancer treatment protocols (Boumahdi and de Sauvage, 2020). In addition, acquired therapy resistance has become an insurmountable obstacle that abolishes the beneficial effects of numerous anti-cancer regimens (De Angelis et al., 2019; Boumahdi and de Sauvage, 2020). Here we report that deficiency of Ku leads to the exploitation of host cells in human cancer cell line models. We found that, upon conditional deletion of XRCC6 that codes for Ku70, HCT116 human colorectal cancer cells gain a parasitic lifestyle that is characterized by the continuous cycle of host cell exploitation. We also found that DAOY cells, a human medulloblastoma cell line, innately lack nuclear Ku70/Ku86 proteins and utilize the host-cell invasion/exit mechanism for maintenance of their survival, similarly to the Ku70 conditionally-null HCT116 cells. Our study demonstrates that a functional loss of Ku protein promotes an adaptive, opportunistic switch to a parasitic lifestyle in human cancer cells, providing evidence for a previously unknown mechanism of cell survival in response to severe genomic stress. We anticipate that our study will bring a new perspective for understanding the mechanisms of cancer cell evolution, leading to a shift in the current concepts of cancer therapy protocols directed to the prevention of cancer metastasis and therapy resistance.

scholarly journals Impact of Alternative Splicing Variants on Liver Cancer Biology

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 18
Author(s):  
Jose J. G. Marin ◽  
Maria Reviejo ◽  
Meraris Soto ◽  
Elisa Lozano ◽  
Maitane Asensio ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Survival Rates ◽  
Splicing Factors ◽  
Aberrant Splicing ◽  
Splicing Variants ◽  
Mrna Maturation ◽  
Available Information ◽  
The Impact

The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.

scholarly journals The Anticancer Drug 3-Bromopyruvate Induces DNA Damage Potentially Through Reactive Oxygen Species in Yeast and in Human Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1161 ◽  
Author(s):  
Magdalena Cal ◽  
Irwin Matyjaszczyk ◽  
Ireneusz Litwin ◽  
Daria Augustyniak ◽  
Rafał Ogórek ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Reactive Oxygen ◽  
Atp Depletion ◽  
Mitochondrial Enzymes ◽  
Oxygen Species ◽  
Human Cancer Cells ◽  
The Impact

3-bromopyruvate (3-BP) is a small molecule with anticancer and antimicrobial activities. 3-BP is taken up selectively by cancer cells’ mono-carboxylate transporters (MCTs), which are highly overexpressed by many cancers. When 3-BP enters cancer cells it inactivates several glycolytic and mitochondrial enzymes, leading to ATP depletion and the generation of reactive oxygen species. While mechanisms of 3-BP uptake and its influence on cell metabolism are well understood, the impact of 3-BP at certain concentrations on DNA integrity has never been investigated in detail. Here we have collected several lines of evidence suggesting that 3-BP induces DNA damage probably as a result of ROS generation, in both yeast and human cancer cells, when its concentration is sufficiently low and most cells are still viable. We also demonstrate that in yeast 3-BP treatment leads to generation of DNA double-strand breaks only in S-phase of the cell cycle, possibly as a result of oxidative DNA damage. This leads to DNA damage, checkpoint activation and focal accumulation of the DNA response proteins. Interestingly, in human cancer cells exposure to 3-BP also induces DNA breaks that trigger H2A.X phosphorylation. Our current data shed new light on the mechanisms by which a sufficiently low concentration of 3-BP can induce cytotoxicity at the DNA level, a finding that might be important for the future design of anticancer therapies.

Enhancement of antiproliferative activity by phototautomerization of anthrylphenols

2015 ◽  
Vol 14 (6) ◽  
pp. 1082-1092 ◽  
Author(s):  
Marijeta Kralj ◽  
Lidija Uzelac ◽  
Yu-Hsuan Wang ◽  
Peter Wan ◽  
Martina Tireli ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Quinone Methide ◽  
Cellular Proteins ◽  
Human Cancer Cells ◽  
The Impact

9-(2-Hydroxyphenyl)anthracene (1) moderately inhibited the proliferation of human cancer cells, but irradiation considerably enhanced the effect due to the formation of quinone methide. The effect is not only due to the damage of DNA, but also due to the impact on the cellular proteins.

scholarly journals Comprehensive characterization and clinical relevance of the SWI/SNF copy number aberrations across human cancers

Hereditas ◽  
2021 ◽  
Vol 158 (1) ◽  
Author(s):  
Zhiwei Xing ◽  
Buhuan Ma ◽  
Weiting Sun ◽  
Yimin Sun ◽  
Caixia Liu
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Therapy Resistance ◽  
The Cancer Genome Atlas ◽  
Dna Damage And Repair ◽  
Human Cancers ◽  
Oncogenic Pathways ◽  
Cancer Types ◽  
Tcga Dataset ◽  
The Impact

Abstract Background Alterations in genes encoding chromatin regulatory proteins are prevalent in cancers and may confer oncogenic properties and molecular changes linked to therapy resistance. However, the impact of copy number alterations (CNAs) of the SWItch/Sucrose NonFermentable (SWI/SNF) complex on the oncogenic and immunologic properties has not been systematically explored across human cancer types. Methods We comprehensively analyzed the genomic, transcriptomic and clinical data of The Cancer Genome Atlas (TCGA) dataset across 33 solid cancers. Results CNAs of the SWI/SNF components were identified in more than 25% of all queried cancers, and tumors harboring SWI/SNF CNAs demonstrated a worse overall survival (OS) than others in several cancer types. Mechanistically, the SCNA events in the SWI/SNF complex are correlated with dysregulated genomic features and oncogenic pathways, including the cell cycle, DNA damage and repair. Notably, the SWI/SNF CNAs were associated with homologous recombination deficiency (HRD) and improved clinical outcomes of platinum-treated ovarian cancer. Furthermore, we observed distinct immune infiltrating patterns and immunophenotypes associated with SWI/SNF CNAs in different cancer types. Conclusion The CNA events of the SWI/SNF components are a key process linked to oncogenesis, immune infiltration and therapeutic responsiveness across human cancers.

scholarly journals Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

2020 ◽  
Vol 21 (11) ◽  
pp. 4002 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Ali Zarrabi ◽  
Kiavash Hushmandi ◽  
Mahshad Kalantari ◽  
Reza Mohammadinejad ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Nuclear Factor Κb ◽  
Molecular Pathways ◽  
Cancer Resistance ◽  
Mesenchymal Transition ◽  
The Impact

Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP chemotherapy has been extensively observed. Among various reported mechanism(s), the epithelial–mesenchymal transition (EMT) process can significantly contribute to chemoresistance by converting the motionless epithelial cells into mobile mesenchymal cells and altering cell–cell adhesion as well as the cellular extracellular matrix, leading to invasion of tumor cells. By analyzing the impact of the different molecular pathways such as microRNAs, long non-coding RNAs, nuclear factor-κB (NF-ĸB), phosphoinositide 3-kinase-related protein kinase (PI3K)/Akt, mammalian target rapamycin (mTOR), and Wnt, which play an important role in resistance exhibited to CP therapy, we first give an introduction about the EMT mechanism and its role in drug resistance. We then focus specifically on the molecular pathways involved in drug resistance and the pharmacological strategies that can be used to mitigate this resistance. Overall, we highlight the various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure.

scholarly journals Mechanistic Insights of Aberrant Splicing with Splicing Factor Mutations Found in Myelodysplastic Syndromes

2021 ◽  
Vol 22 (15) ◽  
pp. 7789
Author(s):  
Naoyuki Kataoka ◽  
Eri Matsumoto ◽  
So Masaki
Keyword(s):  
Myelodysplastic Syndrome ◽  
Regulatory Elements ◽  
Mrna Splicing ◽  
Driver Mutations ◽  
Splicing Factors ◽  
Aberrant Splicing ◽  
Order Of Accuracy ◽  
Splicing Regulators ◽  
Risk Of Progression ◽  
Splicing Patterns

Pre-mRNA splicing is an essential process for gene expression in higher eukaryotes, which requires a high order of accuracy. Mutations in splicing factors or regulatory elements in pre-mRNAs often result in many human diseases. Myelodysplastic syndrome (MDS) is a heterogeneous group of chronic myeloid neoplasms characterized by many symptoms and a high risk of progression to acute myeloid leukemia. Recent findings indicate that mutations in splicing factors represent a novel class of driver mutations in human cancers and affect about 50% of Myelodysplastic syndrome (MDS) patients. Somatic mutations in MDS patients are frequently found in genes SF3B1, SRSF2, U2AF1, and ZRSR2. Interestingly, they are involved in the recognition of 3′ splice sites and exons. It has been reported that mutations in these splicing regulators result in aberrant splicing of many genes. In this review article, we first describe molecular mechanism of pre-mRNA splicing as an introduction and mainly focus on those four splicing factors to describe their mutations and their associated aberrant splicing patterns.

scholarly journals Aberrant splicing isoforms detected by full-length transcriptome sequencing as transcripts of potential neoantigens in non-small cell lung cancer

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Miho Oka ◽  
Liu Xu ◽  
Toshihiro Suzuki ◽  
Toshiaki Yoshikawa ◽  
Hiromi Sakamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Small Cell ◽  
Full Length ◽  
Small Cell Lung ◽  
Aberrant Splicing ◽  
Long Read ◽  
Splicing Isoforms ◽  
Hla Molecules

Abstract Background Long-read sequencing of full-length cDNAs enables the detection of structures of aberrant splicing isoforms in cancer cells. These isoforms are occasionally translated, presented by HLA molecules, and recognized as neoantigens. This study used a long-read sequencer (MinION) to construct a comprehensive catalog of aberrant splicing isoforms in non-small-cell lung cancers, by which novel isoforms and potential neoantigens are identified. Results Full-length cDNA sequencing is performed using 22 cell lines, and a total of 2021 novel splicing isoforms are identified. The protein expression of some of these isoforms is then validated by proteome analysis. Ablations of a nonsense-mediated mRNA decay (NMD) factor, UPF1, and a splicing factor, SF3B1, are found to increase the proportion of aberrant transcripts. NetMHC evaluation of the binding affinities to each type of HLA molecule reveals that some of the isoforms potentially generate neoantigen candidates. We also identify aberrant splicing isoforms in seven non-small-cell lung cancer specimens. An enzyme-linked immune absorbent spot assay indicates that approximately half the peptide candidates have the potential to activate T cell responses through their interaction with HLA molecules. Finally, we estimate the number of isoforms in The Cancer Genome Atlas (TCGA) datasets by referring to the constructed catalog and found that disruption of NMD factors is significantly correlated with the number of splicing isoforms found in the TCGA-Lung Adenocarcinoma data collection. Conclusions Our results indicate that long-read sequencing of full-length cDNAs is essential for the precise identification of aberrant transcript structures in cancer cells.

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