A Review on The Role of VEGF in Tamoxifen Resistance

Background: Certain molecular deviations can lead to the development of breast cancer. For instance, estrogen and estrogen receptors play a significant role in inducing tumor proliferation. However, the efficacy of endocrine therapy through the administration of anti-estrogen drugs, such as Tamoxifen, is challenged by acquired resistance. Methods: Relevant articles were retrieved from Medline and google scholar. All were screened to select the ones discussing the molecular mechanisms of angiogenesis and Tamoxifen resistance. The molecular interactions contributing in the resistant network were studied from the eligible articles. Results: Tamoxifen resistance occurs as a consequence of over-activated signal transduction pathways such as RTK s dependent cascades. It has been shown that microvessel count was greater in Tamoxifen resistant tissues than in responsive ones. Conclusion: In this review, the interaction between estrogen, Tamoxifen, VEGF, and VEGF receptors (VEGFRs) in Tamoxifen resistant cells has been discussed. VEGF and estrogen-independent growth cascades, especially MAPK have a positive feedback loop in Tamoxifen resistant cells. It has been proposed that over-activated pathways in Tamoxifen resistant cells induce pin1 mediated VEGF over-expression, which in turn result in enhanced activation of MAPK.

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The p53/miR-34a/SIRT1 Positive Feedback Loop in Quercetin-Induced Apoptosis

Cellular Physiology and Biochemistry ◽

10.1159/000374024 ◽

2015 ◽

Vol 35 (6) ◽

pp. 2192-2202 ◽

Cited By ~ 48

Author(s):

Guohua Lou ◽

Yanning Liu ◽

Shanshan Wu ◽

Jihua Xue ◽

Fan Yang ◽

...

Keyword(s):

Cell Apoptosis ◽

Feedback Loop ◽

Molecular Mechanisms ◽

Rt Pcr ◽

Cycle Arrest ◽

Anticancer Effects ◽

Huh7 Cells ◽

Mirnas Expression ◽

Induced Apoptosis

Background: The anti-tumor effects of quercetin have been reported, but the underlying molecular mechanisms remain to be elucidated. The aim of present study was to explore the role of miRNA in the anticancer effects of quercetin. Methods: The differential miRNAs expression between the HepG2 and Huh7 cells treated by quercetin were detected by microarray. The xCELLigence, Flow cytometry, RT-PCR and Western blot were used to analyze the cell proliferation, cell apoptosis, cell cycle arrest, anti-tumor genes, and protein expression. Results: miR-34a was up-regulated in HepG2 cells treated by quercetin exhibiting wild-type p53. When inhibiting the miR-34a, the sensitivity of the cells to quercetin decreased and the expression of the SIRT1 was up-regulated, but the acetylation of p53 and the expression of some genes related to p53 down-regulated. Conclusion: miR-34a plays an important role in the anti-tumor effects of querctin in HCC, miR-34a may be a tiemolecule between the p53 and SIRT1 and is composed of a p53/miR-34a/SIRT1 signal feedback loop, which could enhance apoptosis signal and significantly promote cell apoptosis.

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Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma

Gut ◽

10.1136/gutjnl-2015-309501 ◽

2015 ◽

Vol 66 (3) ◽

pp. 530-540 ◽

Cited By ~ 73

Author(s):

Victoria Tovar ◽

Helena Cornella ◽

Agrin Moeini ◽

Samuel Vidal ◽

Yujin Hoshida ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Growth Factor ◽

Molecular Mechanisms ◽

Acquired Resistance ◽

Gene Signature ◽

Signalling Pathways ◽

Fgf Signalling

ObjectiveSorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance.DesignHCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts.ResultsSorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC).ConclusionsAcquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.

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miR-489 confines uncontrolled estrogen signaling through a negative feedback mechanism and regulates tamoxifen resistance in breast cancer

10.21203/rs.3.rs-131460/v1 ◽

2020 ◽

Author(s):

Mithil Soni ◽

Ozge Saatci ◽

Yogin Patel ◽

Manikanda Raja Keerthi Raja ◽

Xinfeng Liu ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cell Lines ◽

Tamoxifen Resistance ◽

Resistant Cell ◽

Estrogen Signaling ◽

Breast Cancers ◽

Tamoxifen Resistant ◽

Hormonal Therapies

Abstract Background Approximately 75% of diagnosed breast cancer tumors are Estrogen receptor (ER) positive tumors and are associated with better prognosis due to their response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. In the current study, we aimed to evaluate miR-489 as a novel molecular target to combat tamoxifen resistance.Methods Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen resistant cell lines unveiled the potential role of miR-489 in regulation of estrogen signaling and development of tamoxifen resistance. We manipulated miR-489 expression in breast cancer cell lines by transient transfection of miR-489 mimic or establishment of knockout cell lines using the CRISPR/Cas9 system to study the reciprocal regulation of miR-489 and estrogen/ER signaling pathways. Cell proliferation, tumor sphere formation assay and flow cytometry analysis were conducted to investigate the role of miR-489 on estrogen-induced cell proliferation, cancer stem cells expansion and development of tamoxifen resistance.Results miR-489 expression was significantly downregulated in tamoxifen-resistant cell lines. Low levels of miR-489 were associated with poor clinical outcomes in patients with hormone treatment. In vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen regulated miRNA that negatively regulated estrogen receptor signaling by using at least the following two mechanisms: i) modulation of ER phosphorylation status by inhibiting MAPK and AKT kinase activities; ii) regulation of nucleus to cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 could break the positive feed-forward loop between estrogen-ERα axis and p38 MAPK in breast cancer cells which was necessary for its function as transcription factor.Conclusion Our study unveiled the underlying molecular mechanism by which miR-489 regulates estrogen signaling pathway through a negative feedback loop and uncovered its role in the development of and overcoming tamoxifen resistance in breast cancers.

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Role of Differentially Expressed Proteins in Acquired Resistance to Cdk4/6 Inhibitor in Breast Cancer

10.21203/rs.3.rs-556331/v1 ◽

2021 ◽

Author(s):

Binayak Kumar ◽

Peeyush Prasad ◽

Ragini Singh ◽

Ram Krishana Sahu ◽

Ashutosh Singh ◽

...

Keyword(s):

Breast Cancer ◽

Drug Targets ◽

Acquired Resistance ◽

Therapy Resistance ◽

Resistant Cell ◽

Molecular Signature ◽

Mcf 7 ◽

Resistant Cells

Abstract CDK4/6 inhibitors (Abemaciclib, Ab and Palbociclib, Pb) stop the G1-phase in cell-cycle being used to cure advanced stage of breast cancer (BC). Acquired resistance is a major challenge in BC therapy. The molecular signature of the therapy resistance for Ab and Pb drugs in BC should be explored. Here, we developed Ab/Pb-resistant cell-models and explored the molecular changes. Drug’s resistance cells were developed in MCF-7 cells by continuous drug treatment and it was confirmed by MTT-assay, PI-staining-microscopy, and real-time-qPCR. Global proteome profiling done by Labelled-free-Proteome-Orbitrap-Fusion-MS-MS technique. Bioinformatics tools used to analyse the proteome data. Ab-resistant and Pb-resistant MCF-7 cells showed increased tolerance for the respective drug. The BCL-2 and MCL-1 survival genes were up-regulated, while the apoptosis genes BAD, BAX, CASP-3 and PARP-1were down-regulated in the resistant cells. Expression of the MDR-1, ABCG2, ESR-1, CDK4, CDK6, and Cyclin-D1 genes were increased in both resistance cells. For proteomics, 237 and 239 proteins were expressed differently in the resistant Ab and Pb cells, respectively. The NUDT5, PEPD, ABAT, ATP1B1, GGCT, and SELENBP1 proteins were down-regulated and the SBSN, HSD17B10, CD9, PDIA3, PSMB4, SLC2A1, and VTN proteins were up-regulated in Ab-resistant cells. The NUDT5, PEPD, and GGCT proteins were down-regulated, while CD47, HIST1H2BN, LMNA, VTN, PSMB5, HBB, PSMA7, FLNB, PRDX4, VDAC1, GOT2, HSPA5, SERPINH1, EIF4A2, FTH, and VIM proteins were up-regulated in Pb-resistant cells. These proteins are a new set of prognostic markers and drug targets for overcoming the respective drug resistance. However, it is necessary to perform an in vivo or clinical assessment.

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A novel tumor suppressor ZBTB1 regulates tamoxifen resistance and aerobic glycolysis through suppressing HER2 expression in breast cancer

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010759 ◽

2020 ◽

Vol 295 (41) ◽

pp. 14140-14152

Author(s):

Panhong Zhang ◽

Yutao Yang ◽

Kai Qian ◽

Lianlian Li ◽

Cuiping Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Dna Repair ◽

Estrogen Receptor ◽

Tumor Suppressor ◽

Cancer Cells ◽

Aerobic Glycolysis ◽

Tamoxifen Resistance ◽

Her2 Expression ◽

Tamoxifen Resistant ◽

Resistant Cells

Transcriptional repressor zinc finger and BTB domain containing 1 (ZBTB1) is required for DNA repair. Because DNA repair defects often underlie genome instability and tumorigenesis, we determined to study the role of ZBTB1 in cancer. In this study, we found that ZBTB1 is down-regulated in breast cancer and this down-regulation is associated with poor outcome of breast cancer patients. ZBTB1 suppresses breast cancer cell proliferation and tumor growth. The majority of breast cancers are estrogen receptor (ER) positive and selective estrogen receptor modulators such as tamoxifen have been widely used in the treatment of these patients. Unfortunately, many patients develop resistance to endocrine therapy. Tamoxifen-resistant cancer cells often exhibit higher HER2 expression and an increase of glycolysis. Our data revealed that ZBTB1 plays a critical role in tamoxifen resistance in vitro and in vivo. To see if ZBTB1 regulates HER2 expression, we tested the recruitments of ZBTB1 on HER2 regulatory sequences. We observed that over-expressed ZBTB1 occupies the estrogen receptor α (ERα)-binding site of the HER2 intron in tamoxifen-resistant cells, suppressing tamoxifen-induced transcription. In an effort to identify potential microRNAs (miRNAs) regulating ZBTB1, we found that miR-23b-3p directly targets ZBTB1. MiR-23b-3p regulates HER2 expression and tamoxifen resistance via targeting ZBTB1. Finally, we found that miR-23b-3p/ZBTB1 regulates aerobic glycolysis in tamoxifen-resistant cells. Together, our data demonstrate that ZBTB1 is a tumor suppressor in breast cancer cells and that targeting the miR-23b-3p/ZBTB1 may serve as a potential therapeutic approach for the treatment of tamoxifen resistant breast cancer.

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Nedd9 Over-Expression Leads to Imatinib Resistance in Gastrointestinal Stromal Tumor Cells.

Blood ◽

10.1182/blood.v110.11.4212.4212 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4212-4212

Author(s):

Thao Le Ba ◽

Vu Hoang Anh ◽

Shigeki Taniguchi ◽

Kazuki Yasuda ◽

Fumiharu Yagasaki ◽

...

Keyword(s):

Cell Proliferation ◽

Synergistic Effect ◽

Focal Adhesion ◽

Src Kinases ◽

Imatinib Resistance ◽

Over Expression ◽

Imatinib Resistant ◽

Src Activation ◽

Resistant Cells

Abstract Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. Most GIST patients respond to imatinib, yet will eventually exhibit resistance. The mechanisms of imatinib resistance have not yet been fully understood. Some mechanisms of secondary resistance are known to be heterogeneous: acquisition of secondary mutation in the KIT or PDGFRA, genomic amplification of KIT and over-expression of the protein and activation of other receptor tyrosine kinases. To explore additional mechanisms of imatinib resistance, we generated imatinib resistant cells from the imatinib sensitive KIT exon 11 mutant GIST-T1 cells, which have deletion of Gly561-Glu579 including Tyr568, a binding site for SRC kinases, by exposing them to increasing concentrations of imatinib for 6 months. Imatinib resistant cells (GIST-T1 IR) became resistant to imatinib with IC50 of 5–7 μM imatinib. GIST-T1 IR cells showed no new mutations in KIT, PDGFRA, PKC𝛉 and JAK2. KIT and its downstream intermediates including AKT, JAK2 remained hyper-activated in GIST-T1 IR with the presence of 1 μM imatinib compared with those in the parental cells. DNA microarray showed over-expression of NEDD9 (neural precursor cell expressed, developmentally down-regulated 9) in resistant cells with 532 fold higher than that in parental cells. NEDD9 also known as HEF1 (human enhancer of filamentation 1) or Cas-L (Crk-associated substrate lymphocyte type) is a docking protein at focal adhesion sites, playing a pivotal role in integrin-mediated signaling which regulates many biological functions, such as cell adhesion, migration, apoptosis, proliferation and differentiation. These cellular functions are known to be related to organogenesis, cancer metastasis, and immune response. FAK (focal adhesion kinase) and SRC kinases are responsible for NEDD9 phosphorylation upon integrin ligation. In GIST-T1 IR cells NEDD9 over-expression and SRC activation were also demonstrated by Western blotting, compared with those in the parental cells. Although imatinib (1 μM) or PP1 (a SRC inhibitor, 25 μM) alone was not enough to suppress SRC activation and its downstream intermediates in GIST-T1 IR cells, the combination of 1 μM imatinib and 10 μM PP1 was able to suppress SRC activation in GIST-T1 IR cells showing a synergistic effect on cell proliferation. Our results for the first time show the causative role of NEDD9 over-expression and SRC activation in imatinib-resistant GIST. These findings can help us to understand the mechanisms of imatinib resistance and the role of SRC inhibitors in treatment of GIST. To achieve durable therapeutic effect in patients with GIST, SRC kinases have to be targeted. Since the combination of KIT and SRC inhibitors completely inhibited SRC phosphorylation showing synergistic effect on cell proliferation compared with those of imatinib or PP1 alone in GIST-T1 IR, this combination should be requisite in treatment regimen of GIST, especially in secondary imatinib-resistant GIST.

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Downregulation of WW domain-containing oxidoreductase leads to tamoxifen-resistance by the inactivation of Hippo signaling

Experimental Biology and Medicine ◽

10.1177/1535370219854678 ◽

2019 ◽

Vol 244 (12) ◽

pp. 972-982 ◽

Cited By ~ 1

Author(s):

Juan Li ◽

Xuefei Feng ◽

Canyu Li ◽

Jie Liu ◽

Pingping Li ◽

...

Keyword(s):

Prognostic Marker ◽

Cause Of Death ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Tamoxifen Resistance ◽

Hippo Signaling ◽

Breast Tumorigenesis ◽

Research Focus ◽

Ww Domain

Acquired tamoxifen-resistance is an important cause of death in patients with hormone-dependent breast tumors. Therefore, understanding the molecular mechanisms underlying the development of tamoxifen-resistance is critical for successful endocrine therapy. This study aimed to define the role of WW domain-containing oxidoreductase (WWOX) in acquired tamoxifen-resistance. Our results show that low WWOX expression was significantly related to tamoxifen-resistance. Moreover, WWOX-knockdown increased resistance to tamoxifen, while WWOX overexpression decreased the resistance. Furthermore, WWOX silencing decreased Yes-associated protein (YAP) phosphorylation and increased YAP nuclear translocation. Finally, YAP silencing decreased tamoxifen-resistance in WWOX-knockdown cells. Our findings demonstrate that WWOX downregulation can lead to the development of tamoxifen-resistance by inactivating Hippo signaling. Thus, WWOX might be a valuable target and prognostic marker for tamoxifen-resistance. Impact statement Understanding the molecular pathways leading to the development of tamoxifen-resistance is an important research focus as acquired tamoxifen-resistance is the main cause of death in patients with benign primary prognosis. Although WW domain-containing oxidoreductase (WWOX) has been related to breast tumorigenesis, its role in acquired tamoxifen-resistance has not yet been demonstrated. Our findings show that WWOX might be a valuable therapeutic target and prognostic marker for tamoxifen-resistance.

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The Potential Role of Lysosomal Sequestration in Sunitinib Resistance of Renal Cell Cancer

Journal of Kidney Cancer and VHL ◽

10.15586/jkcvhl.2015.44 ◽

2016 ◽

Vol 2 (4) ◽

pp. 195-203 ◽

Cited By ~ 10

Author(s):

Kaamar Azijli ◽

Kristy J Gotink ◽

Henk M.W Verheul

Keyword(s):

Renal Cell ◽

Molecular Mechanisms ◽

Kinase Inhibitor ◽

Cell Cancer ◽

Acquired Resistance ◽

Resistance Mechanism ◽

Tumor Type ◽

Von Hippel Lindau ◽

Line Drug

Renal cell carcinoma (RCC) is a highly vascularized tumor type, which is often associated with inactivated mutations in the von Hippel-Lindau gene that drives proangiogenic signaling pathways. As such, new therapies for the treatment of RCC have largely been focused on blocking angiogenesis. Sunitinib, an antiangiogenic tyrosine kinase inhibitor, is the most frequently used first-line drug for the treatment of RCC. Although treatment with sunitinib improves patient outcome considerably, acquired resistance will emerge in all cases. The molecular mechanisms of resistance to sunitinib are poorly understood, but in the past decade, several of these have been proposed. Lysosomal sequestration of sunitinib was reported as a potential resistance mechanism to sunitinib. In this review, the underlying molecular mechanisms of lysosomal sunitinib sequestration and the potential strategies to overcome this resistance are discussed to be able to further improve the treatment of RCC.

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Molecular studies into cell biological role of Copine-4 in Retinal Ganglion Cells

PLoS ONE ◽

10.1371/journal.pone.0255860 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0255860

Author(s):

Manvi Goel ◽

Angel M. Aponte ◽

Graeme Wistow ◽

Tudor C. Badea

Keyword(s):

Retinal Ganglion Cells ◽

Molecular Mechanisms ◽

Ganglion Cells ◽

Mass Spectrometry Analysis ◽

Hek293 Cells ◽

Retinal Cell ◽

Interacting Proteins ◽

Retinal Ganglion ◽

Over Expression

The molecular mechanisms underlying morphological diversity in retinal cell types are poorly understood. We have previously reported that several members of the Copine family of Ca-dependent membrane adaptors are expressed in Retinal Ganglion Cells and transcriptionally regulated by Brn3 transcription factors. Several Copines are enriched in the retina and their over-expression leads to morphological changes -formation of elongated processes-, reminiscent of neurites, in HEK293 cells. However, the role of Copines in the retina is largely unknown. We now investigate Cpne4, a Copine whose expression is restricted to Retinal Ganglion Cells. Over-expression of Cpne4 in RGCs in vivo led to formation of large varicosities on the dendrites but did not otherwise visibly affect dendrite or axon formation. Protein interactions studies using yeast two hybrid analysis from whole retina cDNA revealed two Cpne4 interacting proteins–Host Cell Factor 1 and Morn2. Mass Spectrometry analysis of retina lysate pulled down using Cpne4 or its vonWillebrand A domain showed 207 interacting proteins. A Gene Ontology analysis of the discovered proteins suggests that Cpne4 is involved in several metabolic and signaling pathways in the retina.

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Role of sphingosine kinase 1 (SphK1) on cetuximab resistance in colorectal cancer models.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13509 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13509-e13509

Author(s):

Roberto Bianco ◽

Roberta Rosa ◽

Lucia Nappi ◽

Luigi Formisano ◽

Vincenzo Damiano ◽

...

Keyword(s):

Colorectal Cancer ◽

Anticancer Agents ◽

Acquired Resistance ◽

Sphingosine Kinase ◽

Sphingosine Kinase 1 ◽

Mutational Status ◽

Resistant Cells

e13509 Background: Although EGFR inhibitors, such as the mAb cetuximab, represent an effective strategy in colorectal cancer (CRC), the clinical use of these agents is limited by intrinsic or acquired resistance. Alterations in the ‘sphingolipid rheostat’, or the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P), due to overactivation of sphingosine kinase 1 (SphK1), have been involved in the regulation of resistance to anticancer agents. Since some studies described cross-talks between SphK1 and EGFR-dependent signalling pathways, we investigated the contribution of SphK1 to cetuximab resistance in CRC models. Methods: We used CRC cell lines with both intrinsic or acquired resistance to cetuximab. In these models, we analyzed SphK1 expression/activation by using different tools, including the available drug fingolimod (FTY720), both in vitro and in vivo. We confirmed our data through a tissue microarray (TMA)-based analysis on CRC tissues. Results: SphK1 is overexpressed in CRC cells resistant to cetuximab. Higher doses of N,N-dimethylsphingosine (DMS), a potent competitive inhibitor of SphK1, are needed to achieve complete enzyme saturation and survival inhibition in resistant cells. Moreover, ceramide induces apoptosis less efficiently in resistant than in sensitive cells, consistently with the idea that increased SphK1 levels mediate S1P synthesis by ceramide in resistant cells. SphK1 contribution to resistance is supported by the demonstration that SphK1 inhibition by DMS or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in wild-type cells confers resistance. Re-sensitization to cetuximab is observed after treatment with fingolimod, a S1P receptor inhibitor, both in vitro and in nude mice xenografted with CRC cells. Finally, a TMA-based analysis on CRC tissues revealed that SphK1 expression is related to K-Ras mutational status, a well-known determinant of cetuximab resistance. Conclusions: Our data could clarify the role of SphK1 in the onset of resistance to cetuximab, thus suggesting SphK1 inhibition as a part of novel targeting strategies for resistant cancer patients.

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