scholarly journals Patient-Derived, Drug-Resistant Colon Cancer Cells Evade Chemotherapeutic Drug Effects via the Induction of Epithelial-Mesenchymal Transition-Mediated Angiogenesis

2020 ◽  
Vol 21 (20) ◽  
pp. 7469 ◽  
Author(s):  
Jin Hong Lim ◽  
Kyung Hwa Choi ◽  
Soo Young Kim ◽  
Cheong Soo Park ◽  
Seok-Mo Kim ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Drug Effects ◽  
Control Group ◽  
Metastatic Colon Cancer ◽  
Drug Resistant ◽  
Colon Cancer Cells ◽  
Mesenchymal Transition ◽  
Mouse Xenograft Model

Cancer cells can exhibit resistance to different anticancer drugs by acquiring enhanced anti-apoptotic potential, improved DNA injury resistance, diminished enzymatic inactivation, and enhanced permeability, allowing for cell survival. However, the genetic mechanisms for these effects are unknown. Therefore, in this study, we obtained drug-sensitive HT-29 cells (commercially) and drug-resistant cancer cells (derived from biochemically and histologically confirmed colon cancer patients) and performed microarray analysis to identify genetic differences. Cellular proliferation and other properties were determined after treatment with oxaliplatin, lenvatinib, or their combination. In vivo, tumor volume and other properties were examined using a mouse xenograft model. The oxaliplatin and lenvatinib cotreatment group showed more significant cell cycle arrest than the control group and groups treated with either agent alone. Oxaliplatin and lenvatinib cotreatment induced the most significant tumor shrinkage in the xenograft model. Drug-resistant and metastatic colon cancer cells evaded the anticancer drug effects via angiogenesis. These findings present a breakthrough strategy for treating drug-resistant cancer.

scholarly journals ATP Synthase Subunit Epsilon Overexpression Promotes Metastasis by Modulating AMPK Signaling to Induce Epithelial-to-Mesenchymal Transition and Is a Poor Prognostic Marker in Colorectal Cancer Patients

2019 ◽  
Vol 8 (7) ◽  
pp. 1070 ◽  
Author(s):  
Yan-Jiun Huang ◽  
Yi-Hua Jan ◽  
Yu-Chan Chang ◽  
Hsing-Fang Tsai ◽  
Alexander TH Wu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Atp Synthase ◽  
Distant Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Xenograft Model ◽  
Metastatic Colon Cancer ◽  
Mesenchymal Transition ◽  
Ampk Signaling ◽  
Mouse Xenograft Model

Metastasis remains the major cause of death from colon cancer. We intend to identify differentially expressed genes that are associated with the metastatic process and prognosis in colon cancer. ATP synthase epsilon subunit (ATP5E) gene was found to encode the mitochondrial F0F1 ATP synthase subunit epsilon that was overexpressed in tumor cells compared to their normal counterparts, while other genes encoding the ATP synthase subunit were repressed in public microarray datasets. CRC cells in which ATP5E was silenced showed markedly reduced invasive and migratory abilities. ATP5E inhibition significantly reduced the incidence of distant metastasis in a mouse xenograft model. Mechanistically, increased ATP5E expression resulted in a prominent reduction in E-cadherin and an increase in Snail expression. Our data also showed that an elevated ATP5E level in metastatic colon cancer samples was significantly associated with the AMPK-AKT-hypoxia-inducible factor-1α (HIF1α) signaling axis; silencing ATP5E led to the degradation of HIF1α under hypoxia through AMPK-AKT signaling. Our findings suggest that elevated ATP5E expression could serve as a marker of distant metastasis and a poor prognosis in colon cancer, and ATP5E functions via modulating AMPK-AKT-HIF1α signaling.

scholarly journals TLR-mediated miR-125b-5p downregulation enhances CD248-induced metastasis and drug resistance in colorectal cancer cells

2019 ◽  
Author(s):  
GA-BIN PARK ◽  
Daejin Kim
Keyword(s):  
Colon Cancer ◽  
Drug Resistance ◽  
Gene Silencing ◽  
Cancer Cells ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Drug Resistant ◽  
Colon Cancer Cells ◽  
Mesenchymal Transition ◽  
Migratory Activity

Abstract Background CD248, also called endosialin or tumor endothelial marker-1 (TEM1), is markedly upregulated in almost all cancers, including colon cancers. Changes in microRNA (miRNA) profiles are one of the direct causes of cancer development and progression. In this study, we investigated whether a change in CD248 expression in colon cancer cells could induce drug resistance after chemotherapy, and we explored the relationship between miR-125b-5p levels and CD248 expression in Toll-like receptor (TLR)-modified chemoresistant colon cancer cells. Methods We identified the one of the downregulated miRNAs in drug-resistant HCT8 cells using Affymetrix Genechip miRNA 4.0 array process and validated the expressional change of chemoresistant HCT-116 and HT-29 cells. Interaction between Sp1 and miR-125b-5p was confirmed by miScript target protector assay. To characterize the underlying mechanisms involved in CD248 expression, we adapted the several biological analysis techniques, including RNA-binding Protein Immunoprecipitation (RIP), migration analysis, real-Time PCR, western blot analysis, and gene silencing using siRNA. Results TLR2/6 and TLR5 upregulation in drug-resistant colon cancer cells contributed to miR-125b-5p downregulation and Sp1-mediated CD248 upregulation via NF-κB activation. Exposure to specific TLR2/6 or TLR5 ligands enhanced the expression of mesenchymal markers as well as the migratory activity of oxaliplatin (Ox)- or 5-fluorouracil (5-Fu)-resistant colon cancer cells. The transfection of a synthetic miR-125b-5p mimic into chemoresistant cells prevented Sp1 and CD248 activation and significantly impaired invasive activity. Furthermore, Sp1 or CD248 gene silencing as well as miR-125b-5p overexpression markedly reversed drug resistance and inhibited epithelial-mesenchymal transition (EMT) in colon cancer cells. Conclusions Taken together, these results suggest that changes in miR-125b-5p levels play an important role in Sp1-mediated CD248 expression and the development of drug resistance in TLR-mutated colon cancer cells.

scholarly journals TUBB4B Downregulation Is Critical for Increasing Migration of Metastatic Colon Cancer Cells

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 810 ◽  
Author(s):  
Sobierajska ◽  
Ciszewski ◽  
Wawro ◽  
Wieczorek-Szukała ◽  
Boncela ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Elongation ◽  
Epithelial Mesenchymal Transition ◽  
Cellular Transformation ◽  
Migration And Invasion ◽  
Metastatic Colon Cancer ◽  
Colon Cancer Cells ◽  
Mesenchymal Transition ◽  
Microscopic Studies

Tumor metastasis, the major problem for clinical oncology in colon cancer treatment, is linked with an epithelial-mesenchymal transition (EMT). The observed cellular transformation in this process is manifested by cell elongation, enhanced cell migration and invasion ability, coordinated by cytoskeleton reorganization. In the present study, we examined the role of tubulin-β4 (TUBB4B) downregulation that occurs during EMT in colon cancer cells, in the modulation of the function of microtubules. Based on biochemical and behavioral analysis (transmigration) we posit that the decrease of the TUBB4B level is critical for microtubule-vimentin interaction and contributes to the maintenance of polarity in migrating cells. The microscopic studies revealed that TUBB4B decrease is accompanied by cell elongation and increased number of matured focal adhesion sites, which is a characteristic of the cell metastatic stage. We also demonstrated faster polymerization of microtubules in cells with a lower level of TUBB4B. Simultaneous TUBB3 upregulation, reported during EMT, acts additively in this process. Our studies suggest that the protein level of TUBB4B could be used as a marker for detection of the preinvasive stages of the colon cancer cells. We also concluded that chemotherapy enriched to increase TUBB4B level and/or to stabilize microtubule polymerization might more effectively prevent metastasis in colon cancer development.

scholarly journals Dual Drug Targeting to Kill Colon Cancer Cells

2021 ◽  
Author(s):  
Antony W Burgess ◽  
Maree C Faux ◽  
Silvia Paola Corona ◽  
Janet Weinstock ◽  
Guillaume Lessene ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Specific Inhibitor ◽  
Colon Cancer Cells ◽  
Colon Adenomas ◽  
Mouse Xenograft Model ◽  
Signaling Inhibitors

Colorectal cancer (CRC) is driven by a small set of oncogenic and tumor suppressor mutations. However, different combinations of mutations often lead to poor tumor responses to individual anti-cancer drugs. We have investigated the anti-proliferative and in vitro cytotoxic activity of pair-wise combinations of inhibitors which target specific signaling pathways. Colon cancer cells in non-adherent cultures were killed more effectively by combinations of pyrvinium pamoate (a Wnt pathway inhibitor) and ABT263 (a pro-apoptotic Bcl-2 family inhibitor) or Ly29004 (a PI3kinase inhibitor). However, in a mouse xenograft model, the formulation and toxicity of the ABT737/PP combination prevent the use of these drugs for treatment of tumors. Fortunately, oral analogues of PP (pyrvinium phosphate, PPh) and ABT737(ABT263) have equivalent activity and can be used for treatment of mice carrying SW620 colorectal cancer xenografts. The PPh/ABT263 induced SW620 tumor cell apoptosis and reduced the rate of SW620 tumor growth. Combinations of Wnt signaling inhibitors and specific inhibitor of pro-survival proteins should be considered for the treatment of precancerous colon adenomas and advanced colorectal cancers with APC mutations.

scholarly journals Cytotoxicity and Apoptosis Effects of Curcumin Analogue (2E,6E)-2,6-Bis(2,3-Dimethoxybenzylidine) Cyclohexanone (DMCH) on Human Colon Cancer Cells HT29 and SW620 In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1261
Author(s):  
Nurul Fattin Che Rahim ◽  
Yazmin Hussin ◽  
Muhammad Nazirul Mubin Aziz ◽  
Nurul Elyani Mohamad ◽  
Swee Keong Yeap ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Curcuma Longa ◽  
Metastatic Colon Cancer ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Sw620 Cell

Colorectal cancer (CRC) is the third most common type of cancer worldwide and a leading cause of cancer death. According to the Malaysian National Cancer Registry Report 2012–2016, colorectal cancer was the second most common cancer in Malaysia after breast cancer. Recent treatments for colon cancer cases have caused side effects and recurrence in patients. One of the alternative ways to fight cancer is by using natural products. Curcumin is a compound of the rhizomes of Curcuma longa that possesses a broad range of pharmacological activities. Curcumin has been studied for decades but due to its low bioavailability, its usage as a therapeutic agent has been compromised. This has led to the development of a chemically synthesized curcuminoid analogue, (2E,6E)-2,6-bis(2,3-dimethoxybenzylidine) cyclohexanone (DMCH), to overcome the drawbacks. This study aims to examine the potential of DMCH for cytotoxicity, apoptosis induction, and activation of apoptosis-related proteins on the colon cancer cell lines HT29 and SW620. The cytotoxic activity of DMCH was evaluated using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) cell viability assay on both of the cell lines, HT29 and SW620. To determine the mode of cell death, an acridine orange/propidium iodide (AO/PI) assay was conducted, followed by Annexin V/FITC, cell cycle analysis, and JC-1 assay using a flow cytometer. A proteome profiler angiogenesis assay was conducted to determine the protein expression. The inhibitory concentration (IC50) of DMCH in SW620 and HT29 was 7.50 ± 1.19 and 9.80 ± 0.55 µg/mL, respectively. The treated cells displayed morphological features characteristic of apoptosis. The flow cytometry analysis confirmed that DMCH induced apoptosis as shown by an increase in the sub-G0/G1 population and an increase in the early apoptosis and late apoptosis populations compared with untreated cells. A higher number of apoptotic cells were observed on treated SW620 cells as compared to HT29 cells. Human apoptosis proteome profiler analysis revealed upregulation of Bax and Bad proteins and downregulation of Livin proteins in both the HT29 and SW620 cell lines. Collectively, DMCH induced cell death via apoptosis, and the effect was more pronounced on SW620 metastatic colon cancer cells, suggesting its potential effects as an antimetastatic agent targeting colon cancer cells.

Role of SPARC in the epithelial mesenchymal transition induced by PTHrP in human colon cancer cells

2021 ◽  
pp. 111253
Author(s):  
Pedro Carriere ◽  
Natalia Calvo ◽  
María Belén Novoa ◽  
Fernanda Lopez-Moncada ◽  
Alexander Riquelme ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Human Colon ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Mesenchymal Transition ◽  
Human Colon Cancer Cells

scholarly journals Prevention of High Glucose-Mediated EMT by Inhibition of Hsp70 Chaperone

2021 ◽  
Vol 22 (13) ◽  
pp. 6902
Author(s):  
Alina D. Nikotina ◽  
Snezhana A. Vladimirova ◽  
Elena Y. Komarova ◽  
Dmitry Alexeev ◽  
Sergey Efremov ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Transcription Factors ◽  
Cell Motility ◽  
Cancer Cells ◽  
High Glucose ◽  
Binding Capacity ◽  
Colon Cancer Cells ◽  
Mesenchymal Transition ◽  
Hsp70 Chaperone ◽  
Migration Capacity

Hyperglycemia may contribute to the progression of carcinomas by triggering epithelial-to-mesenchymal transition (EMT). Some proteostasis systems are involved in metastasis; in this paper, we sought to explore the mechanism of Hsp70 chaperone in EMT. We showed that knockdown of Hsp70 reduced cell migration capacity concomitantly with levels of mRNA of the Slug, Snail, and Twist markers of EMT, in colon cancer cells incubated in high glucose medium. Conversely, treatment of cells with Hsp70 inducer U-133 were found to elevate cell motility, along with the other EMT markers. To prove that inhibiting Hsp70 may reduce EMT efficiency, we treated cells with a CL-43 inhibitor of the HSF1 transcription factor, which lowered Hsp70 and HSF1 content in the control and induced EMT in carcinoma cells. Importantly, CL-43 reduced migration capacity, EMT-linked transcription factors, and increased content of epithelial marker E-cadherin in colon cancer cells of three lines, including one derived from a clinical sample. To prove that Hsp70 chaperone should be targeted when inhibiting the EMT pathway, we treated cancer cells with 2-phenylethynesulfonamide (PES) and demonstrated that the compound inhibited substrate-binding capacity of Hsp70. Furthermore, PES suppressed EMT features, cell motility, and expression of specific transcription factors. In conclusion, the Hsp70 chaperone machine efficiently protects mechanisms of the EMT, and the safe inhibitors of the chaperone are needed to hamper metastasis at its initial stage.

Exosome-mediated delivery of functionally active miRNA-375-3p mimic regulate epithelial mesenchymal transition (EMT) of colon cancer cells

Life Sciences ◽  
2021 ◽  
Vol 269 ◽  
pp. 119035
Author(s):  
Ramazan Rezaei ◽  
Kaveh Baghaei ◽  
Davar Amani ◽  
Andrea Piccin ◽  
Seyed Mahmoud Hashemi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Colon Cancer Cells ◽  
Mesenchymal Transition

scholarly journals Deacetylase Plus Bromodomain Inhibition Downregulates ERCC2 and Suppresses the Growth of Metastatic Colon Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1438
Author(s):  
Sabeeta Kapoor ◽  
Trace Gustafson ◽  
Mutian Zhang ◽  
Ying-Shiuan Chen ◽  
Jia Li ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Excision Repair ◽  
Critical Role ◽  
Rat Colon ◽  
Precision Oncology ◽  
Metastatic Colon Cancer ◽  
Colon Cancer Cells ◽  
Combination Drug ◽  
Human Colon Cancer

There is growing evidence that DNA repair factors have clinical value for cancer treatment. Nucleotide excision repair (NER) proteins, including excision repair cross-complementation group 2 (ERCC2), play a critical role in maintaining genome integrity. Here, we examined ERCC2 expression following epigenetic combination drug treatment. Attention was drawn to ERCC2 for three reasons. First, from online databases, colorectal cancer (CRC) patients exhibited significantly reduced survival when ERCC2 was overexpressed in colon tumors. Second, ERCC2 was the most highly downregulated RNA transcript in human colon cancer cells and rat tumors after treatment with the histone deacetylase 3 (HDAC3) inhibitor sulforaphane (SFN) plus JQ1, which is an inhibitor of the bromodomain and extraterminal domain (BET) family. Third, as reported here, RNA-sequencing of polyposis in rat colon (Pirc) polyps following treatment of rats with JQ1 plus 6-methylsulfinylhexyl isothiocyanate (6-SFN) identified Ercc2 as the most highly downregulated gene. The current work also defined promising second-generation epigenetic drug combinations with enhanced synergy and efficacy, especially in metastasis-lineage colon cancer cells cultured as 3D spheroids and xenografts. This investigation adds to the growing interest in combination approaches that target epigenetic ‘readers’, ‘writers’, and ‘erasers’ that are deregulated in cancer and other pathologies, providing new avenues for precision oncology and cancer interception.

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