Exosome‐delivered circRNA promotes glycolysis to induce chemoresistance through the miR‐122‐PKM2 axis in colorectal cancer

Molecular Oncology, Journal Year: 2020, Volume and Issue: 14(3), P. 539 - 555

Published: Jan. 4, 2020

Malignant tumors, including colorectal cancer (CRC), usually rely on ATP generation through aerobic glycolysis for both rapid growth and chemotherapy resistance. The M2 isoform of pyruvate kinase (PKM2) has a key role in catalyzing glycolysis, PKM2 expression varies even within single tumor. In this study, we confirmed that is heterogeneous CRC cells, namely high oxaliplatin-resistant cells but relatively low sensitive found chemoresistant had enhanced production. addition, report PKM2-dependent mechanism which chemosensitive may gradually transform into cells. circular RNA hsa_circ_0005963 (termed ciRS-122 study), was determined to be sponge the PKM2-targeting miR-122, positively correlated with chemoresistance. vitro vivo studies showed exosomes from delivered thereby promoting drug resistance miR-122 sponging upregulation. Moreover, si-ciRS-122 transported by could suppress reverse oxaliplatin regulating ciRS-122-miR-122-PKM2 pathway vivo. Exosomes derived transfer across promote reduce susceptibility This intercellular signal delivery suggests potential novel therapeutic target establishes foundation future clinical applications drug-resistant CRC.

Language: Английский

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Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Nov. 24, 2020

Abstract Wnt signaling is a highly conserved pathway that plays critical role in controlling embryonic and organ development, as well cancer progression. Genome-wide sequencing gene expression profile analyses have demonstrated involved mainly the processes of breast proliferation metastasis. The most recent studies indicated also crucial immune microenvironment regulation, stemness maintenance, therapeutic resistance, phenotype shaping, etc. Wnt/β-Catenin, Wnt–planar cell polarity (PCP), Wnt–Ca 2+ are three well-established pathways share overlapping components play different roles In this review, we summarize main findings concerning relationship between provide an overview existing mechanisms, challenges, potential opportunities for advancing therapy diagnosis cancer.

Language: Английский

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The epigenetic basis of cellular heterogeneity

Nature Reviews Genetics, Journal Year: 2020, Volume and Issue: 22(4), P. 235 - 250

Published: Nov. 26, 2020

Language: Английский

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WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Dec. 20, 2019

WNT/beta-catenin signaling is involved in many physiological processes. Its implication embryonic development, cell migration and polarization has been shown. Nevertheless, alterations this have also related with pathological events such as sustaining proliferating the cancer stem cells (CSCs) subset present tumor bulk. Related this, WNT associated maintenance, expansion epithelial-mesenchymal transition of cells, furthermore two distinctive features population: therapeutic resistance (MDR, multidrug resistance) immune escape. These mechanisms are developed maintained by activation through transcriptional control genes This review focuses on description best known pathways molecules them. Special attention given to cascade proteins deregulated tumors which a decisive role survival. Some these function extrusion pumps that, course chemotherapy, expel drugs outside cells; others help tumoral hide from effector mechanisms. Among targets drug resistance, pump MDR-1 (P-GP, ABCB1) adhesion CD44 family highlighted. The chemokine CCL4 checkpoint CD47 PD-L1 included list target immunity pathway should be main therapy since essential for progression survival, even presence anti-tumoral response and/or antineoplastic drugs. appropriate design combination strategies based modulation mediators protein could negatively affect growth improving efficacy type therapies.

Language: Английский

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Cancer stem cells (CSCs): metabolic strategies for their identification and eradication

Biochemical Journal, Journal Year: 2018, Volume and Issue: 475(9), P. 1611 - 1634

Published: May 9, 2018

Phenotypic and functional heterogeneity is one of the most relevant features cancer cells within different tumor types responsible for treatment failure. Cancer stem (CSCs) are a population with cell-like properties that considered to be root cause heterogeneity, because their ability generate full repertoire cell types. Moreover, CSCs have been invoked as main drivers metastatic dissemination therapeutic resistance. As such, targeting may useful strategy improve effectiveness classical anticancer therapies. Recently, metabolism has player in CSC biology, indeed, oncogenic alterations trigger metabolite-driven CSCs. More interestingly, action metabolic pathways maintenance might not merely consequence genomic alterations. Indeed, certain metabotypic phenotypes play causative role maintaining traits, acting an orchestrator stemness. Here, we review current studies on CSCs, focusing biochemical energy involved propagation. We provide detailed overview plastic behavior response microenvironment changes, genetic aberrations, pharmacological stressors. In addition, describe potential comprehensive approaches identify selectively eradicate together possibility ‘force’ dependences, order effectively target such inflexibilities. Finally, focus mitochondria halt cancer.

Language: Английский

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Emerging role of tumor cell plasticity in modifying therapeutic response

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Oct. 7, 2020

Abstract Resistance to cancer therapy is a major barrier management. Conventional views have proposed that acquisition of resistance may result from genetic mutations. However, accumulating evidence implicates key role non-mutational mechanisms underlying drug tolerance, the latter which focus will be discussed here. Such processes are largely driven by tumor cell plasticity, renders cells insusceptible drug-targeted pathway, thereby facilitating survival and growth. The concept plasticity highlights significance re-activation developmental programs closely correlated with epithelial–mesenchymal transition, properties stem cells, trans-differentiation potential during exposure. From observations in various cancers, this provides an opportunity for investigating nature anticancer resistance. Over years, our understanding emerging phenotype switching modifying therapeutic response has considerably increased. This expanded knowledge contributes developing novel strategies or combination regimens using available drugs, likely improve patient outcomes clinical practice.

Language: Английский

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Drug Resistance in Non-Small Cell Lung Cancer: A Potential for NOTCH Targeting?

Frontiers in Oncology, Journal Year: 2018, Volume and Issue: 8

Published: July 24, 2018

Drug resistance is a major cause for therapeutic failure in non-small cell lung cancer (NSCLC) leading to tumor recurrence, and disease progression. Cell intrinsic mechanisms of include changes the expression drug transporters, activation pro-survival anti-apoptotic pathways, as well non-intrinsic influences microenvironment. It has become evident that tumors are composed heterogeneous population cells with different genetic, epigenetic, phenotypic characteristics results diverse responses therapy underlies emergence resistant clones. This heterogeneity driven by subpopulations termed stem (CSCs) have initiating capabilities, highly self-renewing, retain ability multi-lineage differentiation. CSCs been identified NSCLC associated chemo- radiotherapy resistance. Stem pathways frequently deregulated implicated recurrence after treatment. Here we focus on Notch signaling pathway, which role maintenance, non-squamous cancer, critically assess potential targeting pathway overcome chemotherapeutic targeted agents using both preclinical clinical evidence.

Language: Английский

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The Role of Cancer Stem Cells in Radiation Resistance

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: Feb. 20, 2020

Cancer stem cells (CSC) are a distinct subpopulation within tumor. They able to self-renew and differentiate possess high capability repair DNA damage, exhibit low levels of reactive oxygen species (ROS), proliferate slowly. These features render CSC resistant various therapies, including radiation therapy (RT). Eradication as many possible is requirement for an effective antineoplastic treatment therefore utmost importance the patient. This makes prime targets any therapeutic approach. Albeit clinical data still scarce, experimental first trials give hope that CSC-based has potential improve treatment, especially tumors known be resistant, such glioblastoma. In this review, we will discuss in context RT, describe mechanisms resistance, examine possibilities biomarkers, new approaches.

Language: Английский

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A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability

Oncogene, Journal Year: 2021, Volume and Issue: 40(9), P. 1609 - 1627

Published: Jan. 19, 2021

Abstract The hostile hypoxic microenvironment takes primary responsibility for the rapid expansion of breast cancer tumors. However, underlying mechanism is not fully understood. Here, using RNA sequencing (RNA-seq) analysis, we identified a hypoxia-induced long noncoding (lncRNA) KB-1980E6.3, which aberrantly upregulated in clinical tissues and closely correlated with poor prognosis patients. enhanced lncRNA KB-1980E6.3 facilitates stem cells (BCSCs) self-renewal tumorigenesis under both vitro vivo. Mechanistically, recruited insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to form KB-1980E6.3/IGF2BP1/c-Myc signaling axis that retained stability c-Myc mRNA through increasing binding IGF2BP1 m6A-modified coding region instability determinant (CRD) mRNA. In conclusion, confirm maintains stemness BCSCs suggest disrupting this might provide new therapeutic target refractory

Language: Английский

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Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment

Endocrine Related Cancer, Journal Year: 2018, Volume and Issue: 25(5), P. R303 - R318

Published: Feb. 28, 2018

Ovarian cancer has poor survival rates due to a combination of diagnosis at advanced disease stages and recurrence as result platinum chemotherapy resistance. High-grade serous ovarian (HGSOC), the most common subtype, is conventionally treated with surgery paclitaxel/carboplatin chemotherapy. Initial response are 60–80%, but eventually majority patients become platinum-resistant subsequent relapses. Extensive research on individual biomarkers resistance revealed many potential targets for development new treatments. While this ongoing, there also epigenetic, DNA repair, genome immune changes characterised in HGSOC that can be targeted current therapies. This review discusses focus targetable alternative treatment combinations those currently used. After decades focused elucidating biological cause resistance, future needs using knowledge overcome cancer.

Language: Английский

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