Oncogenic Kras-mediated resistance to chemotherapy via increased ADAM17 activity and ligand shedding in colorectal cancer.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. e14104-e14104
Author(s):  
S. Van Schaeybroeck ◽  
J. Kyula ◽  
D. Longley ◽  
P. Johnston
Keyword(s):  
Colorectal Cancer ◽  
Ligand Shedding ◽  
Resistance To Chemotherapy

scholarly journals TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Sha Zhou ◽  
Jianhong Peng ◽  
Liuniu Xiao ◽  
Caixia Zhou ◽  
Yujing Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Free Survival ◽  
Free Survival ◽  
Epigenetic Regulator ◽  
Crc Management ◽  
Disease Free ◽  
Resistance To Chemotherapy

AbstractResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

scholarly journals Clarithromycin inhibits autophagy in colorectal cancer by regulating the hERG1 potassium channel interaction with PI3K

2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Giulia Petroni ◽  
Giacomo Bagni ◽  
Jessica Iorio ◽  
Claudia Duranti ◽  
Tiziano Lottini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Therapeutic Option ◽  
Autophagic Flux ◽  
Macromolecular Complex ◽  
Human Colorectal Cancer ◽  
Akt Phosphorylation ◽  
Channel Interaction ◽  
Dependent Cell ◽  
Resistance To Chemotherapy

AbstractWe have studied how the macrolide antibiotic Clarithromycin (Cla) regulates autophagy, which sustains cell survival and resistance to chemotherapy in cancer. We found Cla to inhibit the growth of human colorectal cancer (CRC) cells, by modulating the autophagic flux and triggering apoptosis. The accumulation of cytosolic autophagosomes accompanied by the modulation of autophagic markers LC3-II and p62/SQSTM1, points to autophagy exhaustion. Because Cla is known to bind human Ether-à-go-go Related Gene 1 (hERG1) K+ channels, we studied if its effects depended on hERG1 and its conformational states. By availing of hERG1 mutants with different gating properties, we found that fluorescently labelled Cla preferentially bound to the closed channels. Furthermore, by sequestering the channel in the closed conformation, Cla inhibited the formation of a macromolecular complex between hERG1 and the p85 subunit of PI3K. This strongly reduced Akt phosphorylation, and stimulated the p53-dependent cell apoptosis, as witnessed by late caspase activation. Finally, Cla enhanced the cytotoxic effect of 5-fluorouracil (5-FU), the main chemotherapeutic agent in CRC, in vitro and in a xenograft CRC model. We conclude that Cla affects the autophagic flux by impairing the signaling pathway linking hERG1 and PI3K. Combining Cla with 5-FU might be a novel therapeutic option in CRC.

scholarly journals Circulating Noncoding RNAs Have a Promising Future Acting as Novel Biomarkers for Colorectal Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Jia-jun Wang ◽  
Xin Wang ◽  
Yong-xi Song ◽  
Jun-hua Zhao ◽  
Jing-xu Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
General Population ◽  
Malignant Tumors ◽  
Noncoding Rnas ◽  
Screening Methods ◽  
Potential Applications ◽  
Novel Biomarkers ◽  
Noninvasive Biomarkers ◽  
Regulatory Functions ◽  
Resistance To Chemotherapy

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, causing a large number of cancer-related deaths each year. Patients are usually diagnosed at advanced and incurable stages due to the lack of suitable screening methods for early detection. Noncoding RNAs (ncRNAs), including small and long noncoding RNAs (lncRNA), are known to have significant regulatory functions, and accumulating evidence suggests that circulating ncRNAs have potential applications as noninvasive biomarkers for diagnosing CRC, evaluating its prognosis, or predicting chemosensitivity in the general population. In this review, we summarize the origins of circulating ncRNAs and provide details of single and multiple circulating ncRNAs that might have roles as diagnostic and prognostic biomarkers in CRC. We end by discussing circulating ncRNAs that may distinguish patients with resistance to chemotherapy.

T1161 BH3 Mimetics Can Overcome Resistance to Chemotherapy in Colorectal Cancer

2010 ◽  
Vol 138 (5) ◽  
pp. S-501-S-502
Author(s):  
Mary D. Cannon ◽  
Caoimhin Concannon ◽  
Suzanne Hector ◽  
Frank E. Murray ◽  
Jochen H. Prehn
Keyword(s):  
Colorectal Cancer ◽  
Bh3 Mimetics ◽  
Resistance To Chemotherapy

scholarly journals RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

2019 ◽  
Vol 18 (5) ◽  
pp. 957-968 ◽  
Author(s):  
Erik T. Goka ◽  
Pallavi Chaturvedi ◽  
Dayrelis T. Mesa Lopez ◽  
Adriana De La Garza ◽  
Marc E. Lippman
Keyword(s):  
Colorectal Cancer ◽  
Chemotherapy Treatment ◽  
Resistance To Chemotherapy

scholarly journals Chemotherapy-induced miR-141/MAP4K4 signaling suppresses progression of colorectal cancer

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Feifei Wang ◽  
Lianmei Zhao ◽  
Juan Zhang ◽  
Zesong Meng ◽  
Chaoxi Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mitogen Activated Protein Kinase ◽  
Chemotherapy Drugs ◽  
Reverse Transcription Quantitative Pcr ◽  
Mitogen Activated Protein ◽  
Resistance To Chemotherapy ◽  
Protein Kinase Kinase

One of the treatment failures for colorectal cancer (CRC) is resistance to chemotherapy drugs. miRNAs have been demonstrated to be a new regulator of pathobiological processes in various tumors. While few studies have explored the specific role of miR-141 in mediating 5-fluorouracil (5-FU) sensitivity of CRC cells, the present study aimed to detect the contribution of miR-141 in 5-FU sensitivity. The CRC cells viability was measured by MTS assay and cell colony forming. The expression of miR-141 and its downstream targets were assessed by reverse transcription quantitative PCR, Western blotting, and immunohistochemistry. The functional assays were conducted using CRC cells and nude mice. At the present study, we found overexpression of miR-141 could inhibit proliferation, migration, tumor-forming and invasive potential of CRC cells in vitro and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was verified as a directed target of miR-141. The combination treatment of miR-141 with 5-FU, directly targetting MAP4K4, could better inhibit invasion and metastasis of CRC cells colony than either one alone. Furthermore, overexpression of miR-141, targetting MAP4K4, enhanced the effected of 5-FU and suppressed the malignant biological behaviors, in vivo. Our findings showed that 5-FU inhibited malignant behavior of human CRC cells in vitro and in vivo by enhancing the efficiency of miR-141. Our data suggested that targetting the miR-141/MAP4K4 signaling pathway could be a potential molecular target that may enhance chemotherapeutic efficacy in the treatment of CRC.

Irreversible JNK blockade overcomes PD-L1-mediated resistance to chemotherapy in colorectal cancer

Oncogene ◽  
2021 ◽  
Author(s):  
Lei Sun ◽  
Árpád V. Patai ◽  
Tara L. Hogenson ◽  
Martin E. Fernandez-Zapico ◽  
Bo Qin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Resistance To Chemotherapy

scholarly journals Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer

2018 ◽  
Vol 115 (26) ◽  
pp. E5990-E5999 ◽  
Author(s):  
Yen-An Tang ◽  
Yu-feng Chen ◽  
Yi Bao ◽  
Sylvia Mahara ◽  
Siti Maryam J. M. Yatim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Treatment Approach ◽  
Hypoxia Inducible Factor ◽  
Intrinsic Resistance ◽  
Molecule Inhibitor ◽  
Potential Biomarker ◽  
Hypoxic Tumor ◽  
Colorectal Cancer Patients ◽  
Resistance To Chemotherapy

Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2−mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.

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