scholarly journals Pyruvate Dehydrogenase Contributes to Drug Resistance of Lung Cancer Cells Through Epithelial Mesenchymal Transition

2022 ◽  
Vol 9 ◽  
Author(s):  
Buse Cevatemre ◽  
Engin Ulukaya ◽  
Egemen Dere ◽  
Sukru Dilege ◽  
Ayhan Ceyda Acilan
Keyword(s):  
Drug Resistance ◽  
Pyruvate Dehydrogenase ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Cell Metabolism ◽  
Careful Consideration ◽  
Mesenchymal Transition ◽  
Cancer Cell Metabolism ◽  
Underlying Mechanisms

Recently, there has been a growing interest on the role of mitochondria in metastatic cascade. Several reports have shown the preferential utilization of glycolytic pathway instead of mitochondrial respiration for energy production and the pyruvate dehydrogenase (PDH) has been considered to be a contributor to this switch in some cancers. Since epithelial mesenchymal transition (EMT) is proposed to be one of the significant mediators of metastasis, the molecular connections between cancer cell metabolism and EMT may reveal underlying mechanisms and improve our understanding on metastasis. In order to explore a potential role for PDH inhibition on EMT and associated drug resistance, we took both pharmacological and genetic approaches, and selectively inhibited or knocked down PDHA1 by using Cpi613 and shPDHA1, respectively. We found that both approaches triggered morphological changes and characteristics of EMT (increase in mesenchymal markers). This change was accompanied by enhanced wound healing and an increase in migration. Interestingly, cells were more resistant to many of the clinically used chemotherapeutics following PDH inhibition or PDHA1 knockdown. Furthermore, the TGFβRI (known as a major inducer of the EMT) inhibitor (SB-431542) together with the PDHi, was effective in reversing EMT. In conclusion, interfering with PDH induced EMT, and more importantly resulted in chemoresistance. Therefore, our study demonstrates the need for careful consideration of PDH-targeting approaches in cancer treatment.

scholarly journals ROR2 Promotes EMT and Necrosis by Hyperactivating ERK in Melanoma

2021 ◽  
Author(s):  
María Victoria Castro ◽  
Gastón Barbero ◽  
María Belen Villanueva ◽  
Jérémie Nsengimana ◽  
Julia Newton-Bishop ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Orphan Receptor ◽  
Loss Of Function ◽  
Western Blots ◽  
Mesenchymal Transition ◽  
Lung Colonization ◽  
Attractive Therapeutic Target ◽  
Underlying Mechanisms

Abstract PurposeReceptor tyrosine kinase-like orphan receptor 2 (ROR2) has been shown to play opposite roles in the progression of different tumor types. In melanoma, ROR2 was shown to associate with a more invasive phenotype and to contribute to experimental lung colonization. However, the underlying mechanisms regulated by ROR2 have not been elucidated. More importantly, it has not been established whether ROR2 is just a marker or a driver of melanoma aggressiveness. MethodsGain and loss-of-function experiments were applied to study the biological function of ROR2 in melanoma. Transwell assays and Western blots were used to evaluate cell migration and both expression and activation of Epithelial-Mesenchymal Transition (EMT) markers and signaling proteins. The role of ROR2 in vivo was assessed in xenotransplantation experiments.ResultsWe describe that ROR2 promotes EMT by inducing cadherin switch and the upregulation of the transcription factors ZEB1, Twist, Slug, Snail, and HIF1A, together with a mesenchymal phenotype and increased migration. ROR2 association with EMT is also observed in melanoma samples. ROR2 exerts these effects by hyperactivating the MAPK/ERK pathway far above the typical high constitutive activity observed in melanoma. ROR2 also promoted EMT, invasion, and necrosis in xenotransplanted mice. This important role of ROR2 translates into melanoma patient’s prognosis since patients with lymph node metastasis displaying elevated ROR2 levels have reduced overall survival and distant metastasis-free survival.Conclusions These results demonstrate that ROR2 contributes to melanoma progression by hyperactivating ERK and inducing EMT and necrosis. Thus, ROR2 can be an attractive therapeutic target for metastatic melanoma.

scholarly journals The role of p53-microRNA 200-Moesin axis in invasion and drug resistance of breast cancer cells

Tumor Biology ◽  
2017 ◽  
Vol 39 (9) ◽  
pp. 101042831771463 ◽  
Author(s):  
Farheen Alam ◽  
Fatima Mezhal ◽  
Hussain EL Hasasna ◽  
Vidhya A Nair ◽  
SR Aravind ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Morphological Changes ◽  
Mutant Cell ◽  
Migration And Invasion ◽  
Wild Type ◽  
Mesenchymal Transition

This study aimed to analyze the expression of microRNAs in relation to p53 status in breast cancer cells and to delineate the role of Moesin in this axis. We used three isogenic breast carcinoma cell lines MCF7 (with wild-type p53), 1001 (MCF7 with mutated p53), and MCF7-E6 (MCF7 in which p53 function was disrupted). MicroRNA expression was analyzed using microarray analysis and confirmed by real-time polymerase chain reaction. The 1001 clone with mutant p53 showed 22 upregulated and 25 downregulated microRNAs. The predicted targets of these 47 microRNAs were >700 human genes belonging to interesting functional groups such as stem cell development and maintenance. The most significantly downregulated microRNAs in the p53-mutant cell line were from the miR-200 family. We focused on miR-200c which targets many transcripts involved in epithelial-to-mesenchymal transition including Moesin. We found that Moesin was expressed in 1001 but not in its p53 wild-type parental MCF7 consistent with the observed mesenchymal features in the 1001, such as vimentin positivity, E-cadherin negativity, and ZEB1 positivity in addition to the morphological changes. After Moesin silencing, the p53-mutant cells 1001 reverted from mesenchymal-to-epithelial phenotype and showed subtle reduction in migration and invasion and loss of ZEB1 and SNAIL expression. Interestingly, Moesin silencing restored the 1001 sensitivity to Doxorubicin. These results indicate that loss of miR-200c, as a consequence of p53 mutation, can upregulate Moesin oncogene and thus promote carcinogenesis. Moesin may play a role in metastasis and drug resistance of breast cancer.

scholarly journals The role of epithelial–mesenchymal transition-regulating transcription factors in anti-cancer drug resistance

2021 ◽  
Author(s):  
Jihye Seo ◽  
Jain Ha ◽  
Eunjeong Kang ◽  
Sayeon Cho
Keyword(s):  
Drug Resistance ◽  
Transcription Factors ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Drug ◽  
Preclinical Studies ◽  
Mesenchymal Transition ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Future Challenges

AbstractThe complex orchestration of gene expression that mediates the transition of epithelial cells into mesenchymal cells is implicated in cancer development and metastasis. As the primary regulator of the process, epithelial-mesenchymal transition-regulating transcription factors (EMT-TFs) play key roles in metastasis. They are also highlighted in recent preclinical studies on resistance to cancer therapy. This review describes the role of three main EMT-TFs, including Snail, Twist1, and zinc-finger E homeobox-binding 1 (ZEB1), relating to drug resistance and current possible approaches for future challenges targeting EMT-TFs.

scholarly journals Mechanistic Insights Delineating the Role of Cholesterol in Epithelial Mesenchymal Transition and Drug Resistance in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Naaziyah Abdulla ◽  
C. Theresa Vincent ◽  
Mandeep Kaur
Keyword(s):  
Drug Resistance ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Cholesterol Metabolism ◽  
Cholesterol Content ◽  
Multi Drug Resistance ◽  
Mesenchymal Transition ◽  
Proposed Model

Despite the significant advancements made in targeted anti-cancer therapy, drug resistance constitutes a multifaceted phenomenon leading to therapy failure and ultimately mortality. Emerging experimental evidence highlight a role of cholesterol metabolism in facilitating drug resistance in cancer. This review aims to describe the role of cholesterol in facilitating multi-drug resistance in cancer. We focus on specific signaling pathways that contribute to drug resistance and the link between these pathways and cholesterol. Additionally, we briefly discuss the molecular mechanisms related to the epithelial-mesenchymal transition (EMT), and the documented link between EMT, metastasis and drug resistance. We illustrate this by specifically focusing on hypoxia and the role it plays in influencing cellular cholesterol content following EMT induction. Finally, we provide a proposed model delineating the crucial role of cholesterol in EMT and discuss whether targeting cholesterol could serve as a novel means of combatting drug resistance in cancer progression and metastasis.

scholarly journals The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1031 ◽  
Author(s):  
Zohar Amsalem ◽  
Tasleem Arif ◽  
Anna Shteinfer-Kuzmine ◽  
Vered Chalifa-Caspi ◽  
Varda Shoshan-Barmatz
Keyword(s):  
Cancer Cell ◽  
Dna Microarrays ◽  
Epithelial Mesenchymal Transition ◽  
Cell Metabolism ◽  
Mitochondrial Protein ◽  
Residual Tumor ◽  
Mesenchymal Transition ◽  
Cancer Hallmarks ◽  
Acetylation State ◽  
Cancer Cell Metabolism

Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial–mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism–epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics.

scholarly journals The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma

2020 ◽  
Vol 11 ◽  
Author(s):  
Song Peng ◽  
Jun Zhang ◽  
Xintao Tan ◽  
Yiqiang Huang ◽  
Jing Xu ◽  
...  
Keyword(s):  
Chromaffin Cells ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Germline Mutations ◽  
Genetic Alterations ◽  
The Road ◽  
Cancer Cell Metabolism ◽  
Underlying Mechanisms ◽  
Lines Of Evidence

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells in the adrenal medulla (PCCs) or extra-adrenal sympathetic or parasympathetic paraganglia (PGLs). About 40% of PPGLs result from germline mutations and therefore they are highly inheritable. Although dysfunction of any one of a panel of more than 20 genes can lead to PPGLs, mutations in genes involved in the VHL/HIF axis including PHD, VHL, HIF-2A (EPAS1), and SDHx are more frequently found in PPGLs. Multiple lines of evidence indicate that pseudohypoxia plays a crucial role in the tumorigenesis of PPGLs, and therefore PPGLs are also known as metabolic diseases. However, the interplay between VHL/HIF-mediated pseudohypoxia and metabolic disorder in PPGLs cells is not well-defined. In this review, we will first discuss the VHL/HIF axis and genetic alterations in this axis. Then, we will dissect the underlying mechanisms in VHL/HIF axis-driven PPGL pathogenesis, with special attention paid to the interplay between the VHL/HIF axis and cancer cell metabolism. Finally, we will summarize the currently available compounds/drugs targeting this axis which could be potentially used as PPGLs treatment, as well as their underlying pharmacological mechanisms. The overall goal of this review is to better understand the role of VHL/HIF axis in PPGLs development, to establish more accurate tools in PPGLs diagnosis, and to pave the road toward efficacious therapeutics against metastatic PPGLs.

Loss of active MEK1-ERK1/2 restores epithelial phenotype and morphogenesis in transdifferentiated MDCK cells

2003 ◽  
Vol 285 (3) ◽  
pp. C652-C661 ◽  
Author(s):  
Herbert Schramek ◽  
Elisabeth Feifel ◽  
Ingrid Marschitz ◽  
Nadejda Golochtchapova ◽  
Gerhard Gstraunthaler ◽  
...  
Keyword(s):  
Protein Expression ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Three Dimensional ◽  
Relative Role ◽  
Collagen Gels ◽  
Mesenchymal Transition ◽  
Epithelial Phenotype ◽  
Erk1 Protein

Constitutive activation of the MAPK/ERK kinase (MEK)1-ERK2 signaling module in Madin-Darby canine kidney (MDCK)-C7 cells disrupts their ability to form cystlike structures in collagen gels and induces an invasive, myofibroblastlike phenotype. However, the reversibility of these cellular events, as well as the relative role of both MEK isoforms (MEK1 and MEK2) and both ERK isoforms (ERK1 and ERK2) during these processes, has not yet been investigated. We now report that loss of constitutively active MEK1 (caMEK1) and, thus, loss of active ERK1/2 in C7caMEK1 cells is associated with increased MEK2 protein expression, reexpression of ERK1 protein, and epithelial redifferentiation of these cells. The morphological changes toward an epithelial phenotype in these revertant cell lines (C7rev4, C7rev5, C7rev7) are reflected by the upregulation of epithelial marker proteins, such as E-cadherin, β-catenin, and cytokeratin, by the loss of α-smooth muscle actin expression, and by the ability of these epithelial revertants to form well-organized spherical cysts when grown in three-dimensional collagen gels. Further evidence for a role of the MEK1-ERK1/2 module in epithelial-mesenchymal transition was obtained from the analysis of two novel, spontaneously transdifferentiated MDCK-C7 cell clones (C7e1 and C7e2 cells). In these clones, increased MEK1/2-ERK1/2 phosphorylation, reduced MEK2 protein expression, and loss of ERK1 protein expression is associated with phenotypic alterations similar to those observed in transdifferentiated C7caMEK1 cells. C7e1 cells at least partially regained some of their epithelial characteristics at higher passages. In contrast, C7e2 cells maintained a transdifferentiated phenotype at high passage, were unable to generate cystlike epithelial structures, and retained invasive properties when grown on a three-dimensional collagen matrix. We conclude that in renal epithelial MDCK-C7 cells, stable epithelial-to-mesenchymal transition (EMT) is associated with loss of ERK1 protein expression, reduced MEK2 protein expression, and increased basal ERK2 phosphorylation. In contrast, loss of active MEK1-ERK1/2 results in increased MEK2 protein expression and reexpression of ERK1 protein, concomitant with the restoration of epithelial phenotype and the ability to form cystic structures.

scholarly journals The Crucial Role of CXCL8 and Its Receptors in Colorectal Liver Metastasis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Yaqin Bie ◽  
Wei Ge ◽  
Zhibin Yang ◽  
Xianshuo Cheng ◽  
Zefeng Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Biological Effects ◽  
Mesenchymal Transition ◽  
Duffy Antigen ◽  
Direct Targeting ◽  
Tumor Types

CXCL8 (also known as IL-8) can produce different biological effects by binding to its receptors: CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC). CXCL8 and its receptors are associated with the development of various tumor types, especially colorectal cancer and its liver metastases. In addition to promoting angiogenesis, proliferation, invasion, migration, and the survival of colorectal cancer (CRC) cells, CXCL8 and its receptors have also been known to induce the epithelial-mesenchymal transition (EMT) of CRC cells, to help them to escape host immunosurveillance as well as to enhance resistance to anoikis, which promotes the formation of circulating tumor cells (CTCs) and their colonization of distant organs. In this paper, we will review the established roles of CXCL8 signaling in CRC and discuss the possible strategies of targeting CXCL8 signaling for overcoming CRC drug resistance and cancer progression, including direct targeting of CXCL8/CXCR1/2 or indirect targeting through the inhibition of CXCL8-CXCR1/2 signaling.

scholarly journals Exosomes and breast cancer drug resistance

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Xingli Dong ◽  
Xupeng Bai ◽  
Jie Ni ◽  
Hao Zhang ◽  
Wei Duan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Drug ◽  
Therapeutic Drug ◽  
Mesenchymal Transition ◽  
Cancer Drug Resistance ◽  
Survival Signaling ◽  
Daunting Challenge

AbstractDrug resistance is a daunting challenge in the treatment of breast cancer (BC). Exosomes, as intercellular communicative vectors in the tumor microenvironment, play an important role in BC progression. With the in-depth understanding of tumor heterogeneity, an emerging role of exosomes in drug resistance has attracted extensive attention. The functional proteins or non-coding RNAs contained in exosomes secreted from tumor and stromal cells mediate drug resistance by regulating drug efflux and metabolism, pro-survival signaling, epithelial–mesenchymal transition, stem-like property, and tumor microenvironmental remodeling. In this review, we summarize the underlying associations between exosomes and drug resistance of BC and discuss the unique biogenesis of exosomes, the change of exosome cargo, and the pattern of release by BC cells in response to drug treatment. Moreover, we propose exosome as a candidate biomarker in predicting and monitoring the therapeutic drug response of BC and as a potential target or carrier to reverse the drug resistance of BC.

Sign in / Sign up

Export Citation Format

Share Document