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Tamoxifen Rechallenge Decreases Metastatic Potential but Increases Cell Viability and Clonogenicity in a Tamoxifen-Mediated Cytotoxicity-Resistant Subline of Human Breast MCF7 Cancer Cells.

ABSTRACT: Background:Drug resistance is frequently found in estrogen receptor-positive (ER+) breast cancer patients during and after prolonged tamoxifen treatment. Although tamoxifen rechallenge has been proposed for treating recurrent breast tumors, the clinical benefit of this treatment is still controversial. The aims of this study are to identify the possible tamoxifen cytotoxicity-resistant subpopulation of MCF7 cells and to determine the effects of tamoxifen rechallenge on these cells. Methods:Western blot analysis was used to determine the expression levels of various epithelial-mesenchymal transition- and cell survival/proliferation-related proteins in MCF7 and MCF7-derived, tamoxifen-mediated cytotoxicity-resistant MCF7-TAM12.5 breast cancer cells. Wound healing, Transwell migration, and invasion assays were used to examine the metastatic potential of cells. Clonogenic assays, trypan blue exclusion assays, and bromodeoxyuridine assays were used to examine clonogenicity and to determine the proliferation rate of cells. Results:We found that MCF7-TAM12.5 cells exhibited higher tolerance to tamoxifen-mediated cytotoxicity, higher metastatic potential, higher expression levels of XIAP, and lower expression levels of ER?/ER?/HER2/Smac than MCF7 cells. In addition, MCF7 cells endogenously expressed Bcl-2?, whereas MCF7-TAM12.5 cells only expressed Bcl-2?. Interestingly, tamoxifen rechallenge decreased the metastatic potential but increased the proliferation and clonogenicity of MCF7-TAM12.5 cells. At the molecular level, tamoxifen rechallenge upregulated the expression of phosphorylated Aurora A and Aurora B kinase in MCF7-TAM12.5 cells. Conclusion:Our findings further support the existence of highly heterogenetic cancer cell populations in ER+ breast tumors. It will be of clinical importance to determine the protein expression and the genetic profiles of tamoxifen-resistant/recurrent ER+ breast tumors to predict the potential effects of tamoxifen readministration in the future.

SUBMITTER: Chang YC

PROVIDER: S-EPMC7338790 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Tamoxifen Rechallenge Decreases Metastatic Potential but Increases Cell Viability and Clonogenicity in a Tamoxifen-Mediated Cytotoxicity-Resistant Subline of Human Breast MCF7 Cancer Cells.

Chang Yung-Chieh YC Cheung Chun Hei Antonio CHA Kuo Yao-Lung YL

Frontiers in cell and developmental biology 20200630

<h4>Background</h4>Drug resistance is frequently found in estrogen receptor-positive (ER<sup>+</sup>) breast cancer patients during and after prolonged tamoxifen treatment. Although tamoxifen rechallenge has been proposed for treating recurrent breast tumors, the clinical benefit of this treatment is still controversial. The aims of this study are to identify the possible tamoxifen cytotoxicity-resistant subpopulation of MCF7 cells and to determine the effects of tamoxifen rechallenge on these c ...[more]

PMID: 32695778

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Project description:Drug resistance is a prevalent phenomenon that decreases the efficacy of cancer treatments and contributes to cancer progression and metastasis. Weakening drug-resistant cancer cells prior to chemotherapy is a potential strategy to combat chemoresistance. One approach to damage resistant cancer cells is modulation of nutritional intake. The combination of nutrient restriction with targeted compound treatment results in pronounced molecular changes. This study provides valuable information about augmenting existing chemotherapeutic regimes with simultaneous glucose restriction and autophagy inhibition in colorectal cancer cells. In this study, we explore the chemical pathways that drive the cellular response to nutrient restriction, autophagy inhibition, and the chemotherapy irinotecan using global quantitative proteomics and imaging mass spectrometry. We determined that significant pathways were altered including autophagy and metabolism via glycolysis, gluconeogenesis, and sucrose degradation. We also found that period circadian clock 2 (PER2), a tumor suppressor protein, was significantly up-regulated only when glucose was restricted with autophagy inhibition and chemotherapy. The upstream regulators of these differentially regulated pathways were determined to have implications in cancer, showing an increase in tumor suppressor proteins and a decrease in nuclear protein 1 (NUPR1) an important protein in chemoresistance. We also evaluated the phenotypic response of these cells and discovered autophagy inhibition and chemotherapy treatment increased apoptosis and decreased cell clonogenicity and viability. When glucose restriction was combined with autophagy inhibition and chemotherapy, all of the phenotypic results were intensified. In sum, our results indicate that glucose metabolism is of great importance in the ability of cancer cells to survive chemotherapy. By weakening cancer cells with glucose restriction and autophagy inhibition prior to chemotherapy, cancer cells become more sensitive to therapy.

Project description:Focal adhesion kinase (FAK) is up-regulated in thyroid cancer and small molecule FAK scaffolding inhibitor, Y15, was shown to decrease cancer growth in vitro and in vivo. We sought to test the effectiveness of Y15 in thyroid cancer cell lines, profile gene expression with Y15 compared with clinical trial FAK inhibitor PF-04554878, and use Y15 in novel drug combinations. Cell viability was decreased in a dose dependent manner in four thyroid cancer cell lines with Y15 and with higher doses in PF-04554878. Y397 FAK and total FAK were decreased with Y15 and decreased less with PF-04554878. Detachment and necrosis were increased in a dose-dependent manner in all cell lines with Y15. Clonogenicity was decreased in a dose-dependent manner for both Y15 and PF-04554878. We compared gene profiles between papillary thyroid cell lines, TPC1, BCPAP and K1, and 380, 109, and 74 genes were significantly >2-fold changed with Y15 treatment, respectively. Common up-regulated genes were involved in apoptosis, cell cycle, transcription and heat shock; down-regulated genes were involved in cell cycle, cell-to-cell interactions, and cancer stem cell markers. We also compared gene profiles of TT cells treated with Y15 versus PF-04554878. Y15 caused 144 genes to change over 4 fold and PF-04554878 caused 208 gene changes >4-fold (p<0.05). Among genes changed 4 fold, 11 were shared between the treatments, including those involved in metabolism, cell cycle, migration and transcription. Y15 demonstrated synergy with PF-04554878 in TT cells and also synergy with Cabozantinib, Sorafenib, Pazopanib, and strong synergy with Sunitinib in resistant K1 cells. This report revealed the biological effect of Y15 inhibitor, detected the unique and common gene signature profiles in response to Y15 in 4 different thyroid cancer cell lines, demonstrated differential response changes with Y15 and PF-04554878 treatment, and showed the synergy of Y15 with PF-04554878, Cabozantinib, Sorafenib, Pazopanib, and Sunitinib.

Project description:BackgroundLignosus tigris, a recently discovered species of the unique Lignosus family, has been traditionally used by the indigenous communities in Peninsular Malaysia to treat various ailments and as an alternative medicine for cancer treatment. The L. tigris cultivar sclerotia (Ligno TG-K) was found to contain numerous bioactive compounds with beneficial biomedicinal properties and the sclerotial extract exhibited potent antioxidant activity. However, the anticancer property of the Ligno TG-K including in vitro and in vivo antitumor effects as well as its anticancer active compounds and the mechanisms has yet to be investigated.MethodsThe cytotoxicity of the Ligno TG-K against human breast (MCF7), prostate (PC3) and lung (A549) adenocarcinoma cell lines was evaluated using MTT cytotoxicity assay. The cytotoxic mechanisms of the active high molecular weight proteins (HMWp) fraction were investigated through detection of caspases activity and apoptotic-related proteins expression by Western blotting. The in vivo antitumor activity of the isolated HMWp was examined using MCF7 mouse xenograft model. Shotgun LC-MS/MS analysis was performed to identify the proteins in the HMWp.Results and discussionCold water extract of the sclerotia inhibited proliferation of MCF7, A549 and PC3 cells with IC50 ranged from 28.9 to 95.0 µg/mL. Bioassay guided fractionation of the extract revealed that HMWp exhibited selective cytotoxicity against MCF7 cells via induction of cellular apoptosis by the activation of extrinsic and intrinsic signaling pathways. HMWp activated expression of caspase-8 and -9 enzymes, and pro-apoptotic Bax protein whilst inhibiting expression of tumor survivor protein, Bcl-2. HMWp induced tumor-cell apoptosis and suppressed growth of tumor in MCF-7 xenograft mice. Lectins, serine proteases, RNase Gf29 and a 230NA deoxyribonuclease are the major cytotoxic proteins that accounted for 55.93% of the HMWp.ConclusionThe findings from this study provided scientific evidences to support the traditional use of the L. tigris sclerotia for treatment of breast cancer. Several cytotoxic proteins with high abundance have been identified in the HMWp of the sclerotial extract and these proteins have potential to be developed into new anticancer agents or as adjunct cancer therapy.

Dataset Information

Tamoxifen Rechallenge Decreases Metastatic Potential but Increases Cell Viability and Clonogenicity in a Tamoxifen-Mediated Cytotoxicity-Resistant Subline of Human Breast MCF7 Cancer Cells.

Publications

Tamoxifen Rechallenge Decreases Metastatic Potential but Increases Cell Viability and Clonogenicity in a Tamoxifen-Mediated Cytotoxicity-Resistant Subline of Human Breast MCF7 Cancer Cells.

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