Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression.

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GLUT5 regulation by AKT1/3-miR-125b-5p downregulation induces migratory activity and drug resistance in TLR-modified colorectal cancer cells

Carcinogenesis ◽

10.1093/carcin/bgaa074 ◽

2020 ◽

Vol 41 (10) ◽

pp. 1329-1340 ◽

Cited By ~ 1

Author(s):

Ga-Bin Park ◽

Jee-Yeong Jeong ◽

Daejin Kim

Keyword(s):

Colon Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Cell Metabolism ◽

Enzyme Activation ◽

Migration And Invasion ◽

Drug Resistant ◽

Cancer Resistance ◽

Colon Cancer Cells ◽

Migratory Activity

Abstract In cancer, resistance to chemotherapy is one of the main reasons for therapeutic failure. Cells that survive after treatment with anticancer drugs undergo various changes, including in cell metabolism. In this study, we investigated the effects of AKT-mediated miR-125b-5p alteration on metabolic changes and examined how these molecules enhance migration and induce drug resistance in colon cancer cells. AKT1 and AKT3 activation in drug-resistant colon cancer cells caused aberrant downregulation of miR-125b-5p, leading to GLUT5 expression. Targeted inhibition of AKT1 and AKT3 restored miR-125b-5p expression and prevented glycolysis- and lipogenesis-related enzyme activation. In addition, restoring the level of miR-125b-5p by transfection with the mimic sequence not only significantly blocked the production of lactate and intracellular fatty acids but also suppressed the migration and invasion of chemoresistant colon cancer cells. GLUT5 silencing with small interfering RNA attenuated mesenchymal marker expression and migratory activity in drug-resistant colon cancer cells. Additionally, treatment with 2,5-anhydro-d-mannitol resensitized chemoresistant cancer cells to oxaliplatin and 5-fluorouracil. In conclusion, our findings suggest that changes in miR-125b-5p and GLUT5 expression after chemotherapy can serve as a new marker to indicate metabolic change-induced migration and drug resistance development.

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The mechanism of human angiosarcoma drug resistance

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9567 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9567-9567

Author(s):

V. Ravi ◽

D. Henry ◽

S. Chen ◽

M. K. Wong

Keyword(s):

Drug Resistance ◽

Endothelial Cells ◽

Cell Migration ◽

Malignant Neoplasm ◽

Therapeutic Strategies ◽

Migration And Invasion ◽

Development Of Resistance ◽

Vegf Pathway ◽

And Function ◽

Invasion Assays

9567 Background: Angiosarcoma (AS) is a malignant neoplasm of endothelial cells. AS has an extremely poor outcome since it can metastasize widely and rapidly becomes chemoresistant. Understanding the mechanism of this resistance is important not only because of the critical need for new therapeutic strategies in sarcoma, but also since it sheds light on important pathways in endothelial growth that may help understand tumor angiogenesis. Methods/Results: We have established and characterized stable pre-chemotherapy (named B8) and chemotherapy-resistant (named D3) angiosarcoma cell lines from an individual patient with primary (non radiated) breast angiosarcoma prior to initiation of chemotherapy and later after development of resistance to adriamycin, ifosfamide, gemcitabine, docetaxel, paclitaxel, interferon, thalidomide and bevacizumab. D3 cells differ dramatically from B8s in morphology and function. Prechemotherapy B8 cells assume a polygonal morphology reminiscent of native endothelial cells, the D3 cells throw out long processes that span several cell lengths, and do not appear to contact-inhibit. Migration and invasion assays confirm the highly motile nature of these cells. Although it is not surprising that the D3 cells were doxorubicin resistant, we found that unlike the B8 cells, the D3 cells actively transcribe VEGF. In keeping with this, D3 cells are relatively more sensitive to growth inhibition by the anti-VEGF drug bevacizumab than chemonaïve B8 cells. Conclusion: These studies reveal two avenues to target chemoresistant human angiosarcoma; via agents affecting cell migration and those agents that target the VEGF pathway. No significant financial relationships to disclose.

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Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells

Biomolecules ◽

10.3390/biom10010079 ◽

2020 ◽

Vol 10 (1) ◽

pp. 79 ◽

Cited By ~ 3

Author(s):

Noothan Jyothi Satheesh ◽

Samson Mathews Samuel ◽

Dietrich Büsselberg

Keyword(s):

Stem Cells ◽

Cancer Research ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Vitamin C ◽

Resistance Mechanism ◽

Immune Defense ◽

The Body ◽

Treatment Modalities ◽

Migration And Invasion

Cancer remains one of the most feared and dreaded diseases in this era of modern medicine, claiming the lives of many, and affecting the quality of life of several others around the globe despite major advances in the diagnosis, treatment, palliative care and the immense resources invested into cancer research. While research in cancer has largely focused on the neoplasm/tumor and the cancerous cells that make up the tumor, more recently, the existence, proliferation, differentiation, migration and invasion of cancer stem cells (CSCs) and the role that CSCs play in tumor initiation, progression, metastasis, drug resistance and relapse/recurrence of the disease has gained widespread interest in cancer research. Although the conventional therapeutic approaches such as surgery, chemotherapy and radiation therapy are effective cancer treatments, very often these treatment modalities fail to target the CSCs, which then later become the source of disease recurrence. A majority of the anti-cancer agents target rapidly dividing cancer cells and normal cells and hence, have side effects that are not expected. Targeting CSCs remains a challenge due to their deviant nature with a low proliferation rate and increased drug resistance mechanism. Ascorbic acid/Vitamin C (Vit.C), a potent antioxidant, is a cofactor for several biosynthetic and gene regulatory enzymes and a vital contributor to immune defense of the body, and was found to be deficient in patients with advanced stages of cancer. Vit.C has gained importance in the treatment of cancer due to its ability to modulate the redox status of the cell and influence epigenetic modifications and significant roles in HIF1α signaling. Studies have reported that intravenous administration of Vit.C at pharmacological doses selectively kills tumor cells and targets CSCs when administered along with chemotherapeutic drugs. In the current article, we provide an in-depth review of how Vit.C plays an important role in targeting CSCs and its possible use as an adjuvant, neoadjuvant or co-treatment in the treatment of cancers.

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Astragaloside IV Induced miR-134 Expression Reduces EMT and Increases Chemotherapeutic Sensitivity by Suppressing CREB1 Signaling in Colorectal Cancer Cell Line SW-480

Cellular Physiology and Biochemistry ◽

10.1159/000482025 ◽

2017 ◽

Vol 43 (4) ◽

pp. 1617-1626 ◽

Cited By ~ 18

Author(s):

Qi Ye ◽

Li Su ◽

Dagui Chen ◽

Wenyi Zheng ◽

Ye Liu

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Cell Migration ◽

Luciferase Reporter ◽

Colorectal Cancer Cell Line ◽

Migration And Invasion ◽

Astragaloside Iv ◽

Mesenchymal Transition ◽

Cell Migration And Invasion ◽

Chemotherapeutic Sensitivity

Background: Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Although chemotherapy is the primary means in colorectal cancer treatment, it is burdenerd by adverse drug effects. Drug-resistance is one of the most important challenges for chemotherapy and epithelial-mesenchymal transition (EMT) plays critical role in the development of drug resistance. Aims: The aim of this study was to investigate the mechanisms underlying the effect of astragaloside IV (AS-IV) on miR-134 expression, EMT and chemotherapeutic sensitivity in CRC. Methods: Cell proliferation, transfection assay, western blot, real-time PCR, cell migration and invasion assay and luciferase reporter assay were used to detect the effects of AS-IV on CRC. Results: AS-IV significantly inhibited CRC cell migration and invasion by inducing miR-134 expression. Moreover, AS-IV and miR-134 increased the sensitivity of CRC tumors to oxaliplatin (OXA) chemotherapy. cAMP responsive element-binding protein 1 (CREB1), which was required for CRC cells migration, invasion and drug sensitivity, was significantly down-regulated by AS-IV. Conclusions: Our results indicated that AS-IV inhibited CRC EMT by inducing miR-134 expression which significantly down-regulated the CREB1 signaling pathway, and therefore increased the sensitivity to chemotherapy. Our findings provided new insight into the mechanisms of chemotherapy-resistant CRC, and may open new therapeutic options in the treatment of this devastating disease.

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

Tumor Biology ◽

10.1177/1010428317714634 ◽

2017 ◽

Vol 39 (9) ◽

pp. 101042831771463 ◽

Cited By ~ 10

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.

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Molecular Targeting of HuR Oncoprotein Suppresses MITF and Induces Apoptosis in Melanoma Cells

Cancers ◽

10.3390/cancers13020166 ◽

2021 ◽

Vol 13 (2) ◽

pp. 166

Author(s):

Rebaz Ahmed ◽

Ranganayaki Muralidharan ◽

Akhil Srivastava ◽

Sarah E. Johnston ◽

Yan D. Zhao ◽

...

Keyword(s):

Cell Cycle ◽

Drug Resistance ◽

Targeted Therapy ◽

Antitumor Activity ◽

Mek Inhibitor ◽

Melanoma Cells ◽

Migration And Invasion ◽

Mutational Status ◽

The Impact

Background: Treatment of metastatic melanoma possesses challenges due to drug resistance and metastases. Recent advances in targeted therapy and immunotherapy have shown clinical benefits in melanoma patients with increased survival. However, a subset of patients who initially respond to targeted therapy relapse and succumb to the disease. Therefore, efforts to identify new therapeutic targets are underway. Due to its role in stabilizing several oncoproteins’ mRNA, the human antigen R (HuR) has been shown as a promising molecular target for cancer therapy. However, little is known about its potential role in melanoma treatment. Methods: In this study, we tested the impact of siRNA-mediated gene silencing of HuR in human melanoma (MeWo, A375) and normal melanocyte cells in vitro. Cells were treated with HuR siRNA encapsulated in a lipid nanoparticle (NP) either alone or in combination with MEK inhibitor (U0126) and subjected to cell viability, cell-cycle, apoptosis, Western blotting, and cell migration and invasion assays. Cells that were untreated or treated with control siRNA-NP (C-NP) were included as controls. Results: HuR-NP treatment significantly reduced the expression of HuR and HuR-regulated oncoproteins, induced G1 cell cycle arrest, activated apoptosis signaling cascade, and mitigated melanoma cells’ aggressiveness while sparing normal melanocytes. Furthermore, we demonstrated that HuR-NP treatment significantly reduced the expression of the microphthalmia-associated transcription factor (MITF) in both MeWo and MITF-overexpressing MeWo cells (p < 0.05). Finally, combining HuR-NP with U0126 resulted in synergistic antitumor activity against MeWo cells (p < 0.01). Conclusion: HuR-NP exhibited antitumor activity in melanoma cells independent of their oncogenic B-RAF mutational status. Additionally, combinatorial therapy incorporating MEK inhibitor holds promise in overriding MITF-mediated drug resistance in melanoma.

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Bcl-xL: A Focus on Melanoma Pathobiology

International Journal of Molecular Sciences ◽

10.3390/ijms22052777 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2777

Author(s):

Anna Maria Lucianò ◽

Ana B. Pérez-Oliva ◽

Victoriano Mulero ◽

Donatella Del Bufalo

Keyword(s):

Drug Resistance ◽

Transcription Factors ◽

Cell Migration ◽

Alternative Splicing ◽

Conformational Flexibility ◽

Response To Therapy ◽

Migration And Invasion ◽

Apoptotic Proteins ◽

Multicellular Organisms ◽

Post Transcriptional Regulation

Apoptosis is the main mechanism by which multicellular organisms eliminate damaged or unwanted cells. To regulate this process, a balance between pro-survival and pro-apoptotic proteins is necessary in order to avoid impaired apoptosis, which is the cause of several pathologies, including cancer. Among the anti-apoptotic proteins, Bcl-xL exhibits a high conformational flexibility, whose regulation is strictly controlled by alternative splicing and post-transcriptional regulation mediated by transcription factors or microRNAs. It shows relevant functions in different forms of cancer, including melanoma. In melanoma, Bcl-xL contributes to both canonical roles, such as pro-survival, protection from apoptosis and induction of drug resistance, and non-canonical functions, including promotion of cell migration and invasion, and angiogenesis. Growing evidence indicates that Bcl-xL inhibition can be helpful for cancer patients, but at present, effective and safe therapies targeting Bcl-xL are lacking due to toxicity to platelets. In this review, we summarized findings describing the mechanisms of Bcl-xL regulation, and the role that Bcl-xL plays in melanoma pathobiology and response to therapy. From these findings, it emerged that even if Bcl-xL plays a crucial role in melanoma pathobiology, we need further studies aimed at evaluating the involvement of Bcl-xL and other members of the Bcl-2 family in the progression of melanoma and at identifying new non-toxic Bcl-xL inhibitors.

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Downregulation of NEAT1 sensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis

10.21203/rs.3.rs-86053/v1 ◽

2020 ◽

Author(s):

Xiaowei Fu ◽

Xueqiang Deng ◽

Weidong Xiao ◽

Bo Huang ◽

Xuan Yi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Drug Resistance ◽

Epithelial To Mesenchymal Transition ◽

Xenograft Model ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Mouse Xenograft ◽

Pancreatic Cancer Cells ◽

Mouse Xenograft Model ◽

Underlying Mechanisms

Abstract BackgroundChemoresistance is a major cause of treatment failure in pancreatic cancer (PC). It has been demonstrated that epithelial-to-mesenchymal transition (EMT) is closely related to drug resistance in PC; however, the underlying mechanisms are not yet fully understood. Recently found evidence has suggested that nuclear-enriched abundant transcript 1 (NEAT1) is involved in the development of chemoresistance. However, the role and mechanism of NEAT1 in PC gemcitabine resistance remain unknown.MethodsTwo independent gemcitabine-resistant (GR) PC cell lines, PANC-1/GR and SW1990/GR, were established. Transwell assays were used to validate whether GR cells acquired EMT. qRT-PCR and western blot were performed to detect the expression levels of NEAT1, miR-506-3p, and ZEB2 in GR cells. MTT and cell apoptosis assays were conducted to evaluate the sensitivity of GR cells to gemcitabine. Rescue experiments were employed to investigate whether NEAT1 mediates drug resistance of GR cells through modulation of the miR-506-3p/ZEB2/EMT axis. Furthermore, a mouse xenograft model was established to confirm these findings.ResultsGR cells displayed markedly enhanced migration and invasion abilities, decreased expression of E-cadherin, and upregulation of N-cadherin, Vimentin, Snail, ZEB1, and ZEB2. Furthermore, elevated expression of NEAT1 was observed in GR cells. Downregulation of NEAT1 sensitized GR cells to gemcitabine. More importantly, we demonstrated that downregulation of NEAT1 enhanced the sensitivity of GR cells to gemcitabine by reversing the EMT process. NEAT1 regulated ZEB2 expression by sponging miR-506-3p, and the function of NEAT1 in GR cells was dependent on miR-506-3p. These findings were further confirmed in a nude mouse xenograft model.ConclusionsTaken together, downregulation of NEAT1 sensitized the GR PC cells to gemcitabine through modulation of the miR-506-3p/ZEB2/EMT axis. These results provide a new direction for improving the chemotherapeutic effects in PC.

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T-cadherin in epithelial ovarian cancer: relationship with cancer progression and drug resistanceT-cadherin in epithelial ovarian cancer: relationship with cancer progression and drug resistance

10.21203/rs.3.rs-18391/v1 ◽

2020 ◽

Author(s):

Yutao Guan ◽

Yi Lin ◽

Fubin Zhang ◽

Ling-ling Zhou ◽

Yang-ping Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Drug Resistance ◽

Ovarian Carcinoma ◽

Epithelial Ovarian Cancer ◽

Cancer Progression ◽

Carcinoma Cell ◽

Ovarian Tumour ◽

Epithelial Ovarian Carcinoma ◽

Migration And Invasion ◽

Benign Ovarian Tumour

Abstract Background: T-cadherin plays a crucial role in maintaining normal tissue structure by regulating specific cell adhesion, cellular recognition and signal transduction. The purpose of this study was to evaluate whether T-cadherin influences epithelial ovarian cancer (EOC) progression, differentiation and drug resistance and its possible mechanisms.Methods: Epithelial ovarian carcinoma (EOC, n=63) and relevant contralateral normal ovarian (CNO, n=41) fresh tissues were collected from epithelial ovarian carcinoma patients, and benign ovarian tumour fresh tissues were collected from 55 patients with benign ovarian tumours. The human epithelial ovarian carcinoma cell line A2780 was cultured. T-cadherin expression was assessed by real-time RT-PCR and Western blotting, and the expression of matrix metalloproteinase-2 (MMP-2) was detected by Western blotting. pcDNA‑T‑cad plasmid technology was used to upregulate T-cadherin expression. In addition, A2780 cell migration and invasion ability, viability, colony formation, proliferation, apoptosis and sensitivity to paclitaxel were measured.Results: T‑cadherin mRNA and protein expression in EOC tissues from EOC patients was significantly downregulated, and there was no significant difference between the matched contralateral normal ovarian fresh tissue from the same patient and the benign ovarian tumour tissues from other patients. The migration and invasion abilities, viability, colony formation, and proliferation were attenuated by restoration of T‑cadherin expression in A2780 cells via pcDNA‑T‑cad transfection; apoptosis, MMP-2 expression and sensitivity to Taxol were also enhanced by restored T‑cadherin expression. The T‑cadherin expression level was well correlated with the clinical characteristics and symptoms of EOC patients, including tumour stage, histology, lymph node metastasis, tumour size, distant metastasis and cisplatin resistance.Conclusions: T‑cadherin participates in the processes of epithelial ovarian carcinoma cell migration, invasion, proliferation, apoptosis and sensitivity to paclitaxel and can regulate the expression of MMP-2. Downregulation of T‑cadherin expression may contribute to epithelial ovarian cancer progression, differentiation and drug resistance.

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