Epigenetic induction of lipocalin 2 expression drives acquired resistance to 5-fluorouracil in colorectal cancer through integrin β3/SRC pathway

Oncogene ◽  
2021 ◽  
Author(s):  
Wenyi Zhang ◽  
Rulu Pan ◽  
Mei Lu ◽  
Qian Zhang ◽  
Ziqi Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Acquired Resistance ◽  
Lipocalin 2 ◽  
Integrin Β3 ◽  
Src Pathway

scholarly journals Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 75
Author(s):  
Paula I. Escalante ◽  
Luis A. Quiñones ◽  
Héctor R. Contreras
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Methylenetetrahydrofolate Reductase ◽  
Epithelial Mesenchymal Transition ◽  
Late Onset ◽  
Dihydropyrimidine Dehydrogenase ◽  
Acquired Resistance ◽  
Potential Effect ◽  
Mesenchymal Transition ◽  
Folfox Chemotherapy

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

Lipocalin 2 expression promotes tumor progression and therapy resistance by inhibiting ferroptosis in colorectal cancer

2021 ◽  
Author(s):  
Nazia Chaudhary ◽  
Bhagya Shree Choudhary ◽  
Sanket Girish Shah ◽  
Nileema Khapare ◽  
Nehanjali Dwivedi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Progression ◽  
Therapy Resistance ◽  
Lipocalin 2

scholarly journals Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

2021 ◽  
Vol 22 (9) ◽  
pp. 5019
Author(s):  
Helena Oliveres ◽  
David Pesántez ◽  
Joan Maurel
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Tyrosine Kinases ◽  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Post Translational Modification ◽  
Mesenchymal Transition ◽  
Igf1r Signaling ◽  
Colorectal Cancer Patients

Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

scholarly journals Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer

2014 ◽  
Vol 6 (224) ◽  
pp. 224ra26-224ra26 ◽  
Author(s):  
S. Misale ◽  
S. Arena ◽  
S. Lamba ◽  
G. Siravegna ◽  
A. Lallo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Acquired Resistance

scholarly journals Cytotoxic Efficacy and Resistance Mechanism of a TRAIL and VEGFA-Peptide Fusion Protein in Colorectal Cancer Models

2021 ◽  
Vol 22 (6) ◽  
pp. 3160
Author(s):  
Michal Kopczynski ◽  
Malgorzata Statkiewicz ◽  
Magdalena Cybulska ◽  
Urszula Kuklinska ◽  
Katarzyna Unrug-Bielawska ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Transmembrane Protein ◽  
Acquired Resistance ◽  
Protein A ◽  
Resistance Mechanism ◽  
Receptor Expression ◽  
Human Colorectal Cancer ◽  
Protein Activity ◽  
Anticancer Efficacy

TNF-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein capable of selectively inducing apoptosis in cancer cells by binding to its cognate receptors. Here, we examined the anticancer efficacy of a recently developed chimeric AD-O51.4 protein, a TRAIL fused to the VEGFA-originating peptide. We tested AD-O51.4 protein activity against human colorectal cancer (CRC) models and investigated the resistance mechanism in the non-responsive CRC models. The quantitative comparison of apoptotic activity between AD-O51.4 and the native TRAIL in nine human colorectal cancer cell lines revealed dose-dependent toxicity in seven of them; the immunofluorescence-captured receptor abundance correlated with the extent of apoptosis. AD-O51.4 reduced the growth of CRC patient-derived xenografts (PDXs) with good efficacy. Cell lines that acquired AD-O51.4 resistance showed a significant decrease in surface TRAIL receptor expression and apoptosis-related proteins, including Caspase-8, HSP60, and p53. These results demonstrate the effectiveness of AD-O51.4 protein in CRC preclinical models and identify the potential mechanism underlying acquired resistance. Progression of AD-O51.4 to clinical trials is expected.

Sulfonamide-Functionalized Polymeric Nanoparticles For Enhanced In Vivo Colorectal Cancer Therapy

2021 ◽  
Vol 18 ◽  
Author(s):  
Pedro Pires Goulart Guimarães ◽  
Celso Tarso Rodrigues Viana ◽  
Luciana Pereira ◽  
Savio Morato Lacerda Gontijo ◽  
Paula Peixoto Campos ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Polymeric Nanoparticles ◽  
Acquired Resistance ◽  
Lung Mass ◽  
Cancer Model ◽  
Liver Mass ◽  
Therapeutic Delivery ◽  
Promising Strategy ◽  
Common Cancer

Background: Colorectal cancer (CRC) is the third most common cancer in the world. 5-Fluorouracil (5-FU) is a conventional and most effective drug used in the clinic for the treatment of CRC. However, the clinical use of 5-FU is limited due to the acquired resistance and systemic toxicity, such as hepatotoxicity and gastrointesti-nal toxicity. Objective: Recent advances in nanomedicine are being exploited to develop nanoparticle platforms to overcome resistance and therapeutic delivery of active molecules. Here, we develop 5-FU loaded sulfadiazine-poly(lactide-co-glycolide) nanoparticles (SUL-PLGA NPs) to be applied in the colorectal cancer model. Methods: We assessed the in vivo efficacy of the SUL-PLGA NPs to enhance the antitumor effect of 5-FU. Results: In vivo treatment with 5-FU-SUL-PLGA NPs significantly reduced tumor growth in a colon cancer xen-ograft model compared to free 5-FU and 5-FU loaded non-targeted NPs. Treatment with 5-FU-SUL-PLGA NPs also increased blood vessel diameters within tumors, which could act in conjunction to enhance antitumor effi-cacy. In addition, 5-FU-SUL-PLGA NPs significantly reduced liver mass and lung mass, which are the most common metastasis sites of CRC, and decreased liver hepatotoxicity compared to free 5-FU drug and 5-FU loaded non-targeted NPs. Conclusion: Our findings suggest that the use of 5-FU-SUL-PLGA NPs is a promising strategy to enhance 5-FU efficacy against CRC.

scholarly journals miR-122 Targets X-Linked Inhibitor of Apoptosis Protein to Sensitize Oxaliplatin-Resistant Colorectal Cancer Cells to Oxaliplatin-Mediated Cytotoxicity

2018 ◽  
Vol 51 (5) ◽  
pp. 2148-2159 ◽  
Author(s):  
Yongqiang Hua ◽  
Yaodong Zhu ◽  
Jijie Zhang ◽  
Zhenfeng Zhu ◽  
Zhouyu Ning ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Acquired Resistance ◽  
Cellular Protein ◽  
Cell Counting ◽  
Inhibitor Of Apoptosis ◽  
Acquired Drug Resistance ◽  
Inhibitor Of Apoptosis Protein ◽  
Ht29 Cells ◽  
Xiap Expression ◽  
Apoptosis Protein

Background/Aims: Although oxaliplatin is one of the most effective chemotherapeutic drugs used to treat colorectal cancer (CRC), long-term administration usually induces acquired drug resistance during the course of treatment. Thus, there is an urgent need to explore novel strategies to improve the efficiency of cancer therapy. The aim of this study was to explore the effect of microRNA-122 (miR-122) on reversing oxaliplatin resistance in CRC. Methods: The expression of miR-122 in CRC cells was examined by quantitative reverse transcriptase real-time PCR. The cytotoxicity of oxaliplatin against CRC cells was evaluated by Cell Counting Kit-8 assays. Mitochondrial membrane potentials and cell apoptotic rates were measured by flow cytometry. Cellular protein expression and interactions were detected by western blot and co-immunoprecipitation. Results: Established oxaliplatin-resistant SW480 and HT29 cells (SW480/OR and HT29/OR) expressed significantly higher levels of X-linked inhibitor of apoptosis protein (XIAP) and lower levels of miR-122 compared with normal SW480 and HT29 cells, respectively. Our results showed that the downregulation of miR-122 was responsible for the overexpression of XIAP in these oxaliplatin-resistant CRC cells. We then found that the recovery of miR-122 expression can sensitize SW480/OR and HT29/OR cells to oxaliplatin-mediated apoptosis through the inhibition of XIAP expression. Conclusion: Upregulation of XIAP in CRC cells is responsible for the acquired resistance to oxaliplatin. Furthermore, miR-122 reversed oxaliplatin resistance in CRC by targeting XIAP.

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