scholarly journals Loss of SHMT2 mediates 5-FU chemoresistance by inducing autophagy in colorectal cancer

2019 ◽  
Author(s):  
Jian Chen ◽  
Guangjian Fan ◽  
Chao Xiao ◽  
Xiao Wang ◽  
Yupeng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Vital Role ◽  
Serine Hydroxymethyltransferase ◽  
Colorectal Carcinogenesis ◽  
Chemotherapeutic Drug ◽  
Xenograft Models ◽  
One Carbon Metabolism

AbstractSerine hydroxymethyltransferase 2 (SHMT2) plays a vital role in one-carbon metabolism and drives colorectal carcinogenesis. In our study, loss of SHMT2 induced 5-Fluorouracil (5-FU) chemoresistance and was associated with poor prognosis in colorectal cancer (CRC). To elucidate the possible mechanism and generate a strategy to sensitize CRC to 5-FU chemotherapy, we first identified the binding proteins of SHMT2 in cancer cells by mass spectrometry. We found that SHMT2 inhibited autophagy through binding cytoplasmic p53. In fact, SHMT2 prevented cytoplasmic p53 degradation by inhibiting the binding of p53 and HDM2. Under treatment with 5-FU, depletion of SHMT2 promoted autophagy and inhibited apoptosis. Autophagy inhibitors CQ decreased low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, we enhanced the lethality of 5-FU treatment to CRC cells through the autophagy inhibitor or knockdown of SHMT2 in patient-derived and CRC cell xenograft models. Our findings identified the low SHMT2-induced autophagy on 5-FU resistance in CRC. These results reveal SHMT2-p53 as a novel cancer therapeutic target to reduce chemotherapeutic drug resistance.

scholarly journals The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy

Oncogene ◽  
2021 ◽  
Author(s):  
Jian Chen ◽  
Risi Na ◽  
Chao Xiao ◽  
Xiao Wang ◽  
Yupeng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Patient Survival ◽  
Serine Hydroxymethyltransferase ◽  
First Line ◽  
Xenograft Models ◽  
Potential Opportunity ◽  
First Line Treatment ◽  
Novel Therapeutic

Abstract5-Fluorouracil (5-FU)-based chemotherapy is the first-line treatment for colorectal cancer (CRC) but is hampered by chemoresistance. Despite its impact on patient survival, the mechanism underlying chemoresistance against 5-FU remains poorly understood. Here, we identified serine hydroxymethyltransferase-2 (SHMT2) as a critical regulator of 5-FU chemoresistance in CRC. SHMT2 inhibits autophagy by binding cytosolic p53 instead of metabolism. SHMT2 prevents cytosolic p53 degradation by inhibiting the binding of p53 and HDM2. Under 5-FU treatment, SHMT2 depletion promotes autophagy and inhibits apoptosis. Autophagy inhibitors decrease low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, the lethality of 5-FU treatment to CRC cells was enhanced by treatment with the autophagy inhibitor chloroquine in patient-derived and CRC cell xenograft models. Taken together, our findings indicate that autophagy induced by low SHMT2 levels mediates 5-FU resistance in CRC. These results reveal the SHMT2–p53 interaction as a novel therapeutic target and provide a potential opportunity to reduce chemoresistance.

scholarly journals FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Weixing Dai ◽  
Xianke Meng ◽  
Shaobo Mo ◽  
Wenqiang Xiang ◽  
Ye Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Poor Prognosis ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Glucose Consumption ◽  
Underlying Mechanism ◽  
Low Expression

Abstract Background Low expression of FOXE1, a member of Forkhead box (FOX) transcription factor family that plays vital roles in cancers, contributes to poor prognosis of colorectal cancer (CRC) patients. However, the underlying mechanism remains unclear. Materials and methods The effects of FOXE1 on the growth of colon cancer cells and the expression of glycolytic enzymes were investigated in vitro and in vivo. Molecular biological experiments were used to reveal the underlying mechanisms of altered aerobic glycolysis. CRC tissue specimens were used to determine the clinical association of ectopic metabolism caused by dysregulated FOXE1. Results FOXE1 is highly expressed in normal colon tissues compared with cancer tissues and low expression of FOXE1 is significantly associated with poor prognosis of CRC patients. Silencing FOXE1 in CRC cell lines dramatically enhanced cell proliferation and colony formation and promoted glucose consumption and lactate production, while enforced expression of FOXE1 manifested the opposite effects. Mechanistically, FOXE1 bound directly to the promoter region of HK2 and negatively regulated its transcription. Furthermore, the expression of FOXE1 in CRC tissues was negatively correlated with that of HK2. Conclusion FOXE1 functions as a critical tumor suppressor in regulating tumor growth and glycolysis via suppressing HK2 in CRC.

scholarly journals UPF1 Promotes Chemoresistance to Oxaliplatin Through Maintenance of Stemness by Increasing Phosphorylated TOP2A in Colorectal Cancer.

2020 ◽  
Author(s):  
Congcong Zhu ◽  
Long Zhang ◽  
Senlin Zhao ◽  
Weixing Dai ◽  
Yun Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cell Lines ◽  
Clinical Relevance ◽  
Poor Prognosis ◽  
Therapy Strategy ◽  
Underlying Mechanisms

Abstract Background: UPF1 is proved to dysregulate in multiple tumors and influence carcinogenesis. However, the role of UPF1 on oxaliplatin resistance in colorectal cancer (CRC) remains unknown.Methods: Firstly, we investigated the clinical relevance of UPF1 in CRC patients. Then, we explored the influence of UPF1 on chemoresistance to oxaliplatin in vitro and in vivo. Finally, we disclosed the underlying mechanisms of oxaliplatin resistance induced by UPF1.Results: UPF1 is upregulated in CRC and overexpression of UPF1 more likely results in recurrence in CRC patients and predicts a poorer overall survival (OS). UPF1 maintains stemness in CRC cell lines and promotes chemoresistance to oxaliplatin in CRC. UPF1-induced oxaliplatin resistance can be associated with interaction with TOP2A and increasing phosphorylated TOP2A.Conclusions: UPF1 was overexpressed and predicted a poor prognosis in CRC. UPF1 enhanced the stemness and chemoresistance to oxaliplatin by interaction with TOP2A and increase of phosphorylated TOP2A in CRC, which may provide a new therapy strategy for chemoresistance to oxaliplatin in CRC patients.

KLF5 Inhibition Overcomes Oxaliplatin Resistance In Patient-Derived Colorectal Cancer Organoids by Restoring Apoptotic Response

2020 ◽  
Author(s):  
Xiaohui Shen ◽  
Han Gao ◽  
Yuchen Zhang ◽  
Zhuoqing Xu ◽  
Wenqing Feng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chromatin Immunoprecipitation ◽  
Combined Treatment ◽  
Luciferase Reporter ◽  
Cancer Drug ◽  
Apoptotic Response ◽  
Cancer Drug Resistance ◽  
Xenograft Models

Abstract Background: Oxaliplatin resistance is a major challenge for treatment of metastatic colorectal cancer (mCRC). Many molecular targeted drugs for refractory CRC have been developed to solve colorectal cancer drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin- resistance still not clear.Methods: PDOs derived from CRC patients were constructed to conduct the sensitivity assays of oxaliplatin in vitro. Oxaliplatin resistant PDOs were selected and treated under the combined treatment of ML264(a KLF5 inhibitor) and oxaliplatin to determine the effects of KLF5 inhibition on apoptosis. Using CRC cell lines to investigate downstream mechanisms and xenograft models to confirm whether ML264 can restore oxaliplatin sensitivity of CRC cells in vivo.Results: We successfully constructed CRC PDOs and conducted the sensitivity test of oxaliplatin in PDOs from different patients. We found that ML264 restores oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signal pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcomed oxaliplatin resistance in xenograft tumors.Conclusions: Our study demonstrated that ML264 can restores oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 might be a potential therapeutic target for CRC resistant to oxaliplatin. PDOs have strong potential in evaluating inhibitors and drug combinations therapy in a preclinical environment.

scholarly journals Prognostic Value and Biological Function of LRRN4 in Colorectal Cancer

2021 ◽  
Author(s):  
Cheng Xu ◽  
Yulin Chen ◽  
Feiwu Long ◽  
Junman Ye ◽  
Xue Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mrna Level ◽  
Biological Significance ◽  
Progression Free Survival ◽  
Molecular Determinant ◽  
Chinese Cohort ◽  
Xenograft Models

Abstract Background: Several nervous and nerve-related biomarkers have been detected in colorectal cancer (CRC) and can contribute to the progression of CRC. However, the role of leucine-rich repeat neuronal 4 (LRRN4), a recently identified neurogenic marker, in CRC remains unclear. Methods: We examined the expression and the clinical outcomes of LRRN4 in CRC from TCGA-COREAD mRNA-sequencing datasets and immunohistochemistry on the Chinese cohort. Furthermore, the colony formation, flow cytometry, wound healing assay and mouse xenograft models were used to investigate the biological significance of LRRN4 in CRC cell lines with LRRN4 knockdown or overexpression in vitro and in vivo. In addition, weighted co-expression network analysis and DAVID were used to explore the potential molecular mechanism. Results: We provide the first evidence that LRRN4 expression, at both the protein and mRNA level, was remarkable high in CRC compared to controls and positively correlated with the clinical outcome of CRC patients. Specifically, LRRN4 was an independent prognostic factor for progression-free survival and overall survival in CRC patients. Further functional experiments showed that LRRN4 promoted cell proliferation, cell DNA synthesis and cell migration and inhibited apoptosis. Knockdown of LRRN4 can correspondingly decrease these effects in vitro and can significantly suppress the growth of xenografts. Several biological functions and signaling pathways were regulated by LRRN4, including proteoglycans in cancer, glutamatergic synapse, Ras, MAPK and PI3K.Conclusions: Our results suggest that LRRN4 could be a biological and molecular determinant to stratify CRC patients into distinct risk categories, and mechanistically, this is likely attributable to LRRN4 in regulating several malignant phenotypes of neoplastic cells via cancer-related pathways.

scholarly journals TRIM25 Regulates Oxaliplatin Resistance in Colorectal Cancer by Promoting EZH2 Stability

2020 ◽  
Author(s):  
Sha Zhou ◽  
Jianhong Peng ◽  
Liuniu Xiao ◽  
Caixia Zhou ◽  
Yujing Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Disease Free Survival ◽  
Annexin V ◽  
Vital Role ◽  
Kaplan Meier

Abstract Background Resistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). TRIM25, an E3-ubiquitin ligase, has been reported to play a vital role in tumorigenesis. This project aims to explore the function and mechanism of TRIM25 in regulating oxaliplatin resistance in colorectal cancer.Methods The expression of TRIM25 in colorectal cancer tissues were examined by publicly available dataset, Immunohistochemistry and western blot. Further survival analysis was conducted using Kaplan-Meier method. CCK8 assay, colony-formation assay, Annexin V-FITC /PI staining and xenograft tumor models were used for evaluating sensitivity of CRC cells to oxaliplatin. Sphere-formation assay, RT-PCR and limiting dilution assay were used to evaluate the influence of TRIM25 on stem cell properties of CRC cells. Co-immunoprecipitation, polyubiquitination assay and western bolt elucidate the mechanism by which TRIM25 regulates EZH2.Results Patients with high expression of TRIM25 have significantly higher recurrence rate (28.9% vs. 15.0%, P = 0.012) and worse disease-free survival (P = 0.006) than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited while TRIM25 overexpression enhanced CRC cells survival after oxaliplatin treatment. In addition, TRIM25 promotes stem cell properties of CRC cells both in vitro and in vivo (8 mice per group). Importantly, we demonstrated that TRIM25 inhibits the binding of E3-ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2 and promoting oxaliplatin resistance. Conclusions Our study provides evidence that TRIM25 is a novel epigenetic regulator of oxaliplatin resistance. Targeting TRIM25 might be a promising strategy for CRC treatment.

scholarly journals Effects of pharmacological calcimimetics on colorectal cancer cells over-expressing the human calcium-sensing receptor

2020 ◽  
Author(s):  
Luca Iamartino ◽  
Taha Elajnaf ◽  
Katharina Gall ◽  
Jacquelina David ◽  
Teresa Manhardt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Tumor Growth ◽  
Colorectal Carcinogenesis ◽  
Inflammatory Factors ◽  
Type Ii ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

AbstractThe calcium-sensing receptor (CaSR) is a ubiquitously expressed multifunctional G protein-coupled receptor. Several studies reported that the CaSR plays an anti-inflammatory and anti-tumorigenic role in the intestine, and that it is down-regulated during colorectal carcinogenesis. We hypothesized that intestine-specific positive allosteric CaSR modulators (type II calcimimetics) could be used for the treatment of intestinal pathologies. Therefore, the aim of this study was to determine the effect of pharmacological stimulation of CaSR on gene expression in vitro and on tumor growth in vivo.We stably transduced two colon cancer cell lines (HT29 and Caco2) with lentiviral vectors containing either the CaSR fused to GFP or GFP only. Using RNA sequencing, RT-qPCR experiments and ELISA, we determined that CaSR over-expression itself had generally little effect on gene expression in these cells. However, treatment with 1μM of the calcimimetic NPS R-568 increased the expression of pro-inflammatory factors such as IL-23α and IL-8 and reduced the transcription of various differentiation markers in the cells over-expressing the CaSR. In vivo, neither the presence of the CaSR nor p.o. treatment of the animals with the calcimimetic cinacalcet affected tumor growth, tumor cell proliferation or tumor vascularization of murine HT29 xenografts.In summary, CaSR stimulation in CaSR over-expressing cells enhanced the expression of inflammatory markers in vitro, but was not able to repress colorectal cancer tumorigenicity in vivo. These findings suggest potential pro-inflammatory effects of the CaSR and type II calcimimetics in the intestine.

scholarly journals B Subunit of Human Chorionic Gonadotropin Promotes Tumor Invasion and Predicts Poor Prognosis of Early-Stage Colorectal Cancer

2018 ◽  
Vol 45 (1) ◽  
pp. 237-249 ◽  
Author(s):  
Jiali Li ◽  
Mingzhu Yin ◽  
Wanjing Song ◽  
Fengyun Cui ◽  
Wei Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Tumor Invasion ◽  
Poor Prognosis ◽  
Early Stage ◽  
Migration And Invasion ◽  
Β Hcg

Background/Aims: It is well established that many non-trophoblastic tumors secrete HCG (human chorionic gonadotropin) and that such secretion is correlated with the poor prognosis of tumor patients. This study aims to analyze the correlation between β-HCG expression and outcome of colorectal cancer (CRC) and understand its role in CRC pathology Methods: We detected the mRNA and protein expression of β-HCG in human CRC tissues with RT-qPCR and immunohistochemistry, and we compared the clinical-pathological characteristics, prognosis and progression between the β-HCG positive and negative groups. We also generated CRC cell lines with β-HCG over-expression as well as β-HCG stable knockout, and evaluated cell function and mechanism in vitro and in vivo. Results: Fifty out of 136 CRC patients (37%) expressed β-HCG at the invasive front. Clinical-pathological data showed that β-HCG was positively correlated with Dukes staging (P=0.031) and lymph node metastasis (P=0.012). Survival analysis suggested that the patients with high expression of β-HCG had poorer prognosis than those with low β-HCG expression (P=0.0289). β-HCG expression level was also positively correlated with tumor invasion in early-stage CRC patient tissues (P=0.0227). Additionally β-HCG promoted the migration and invasion of CRC in vitro and in vivo but had no effect on the proliferation of tumor cells. Conclusion: Our study demonstrated that β-HCG was ectopically expressed in the CRC patients and its high expression correlated with poor prognosis of early-stage CRC. Additionally it worked as an oncogene that promotes the migration and invasion of CRC by epithelial-mesenchymal transition (EMT).

scholarly journals CORO1C is Associated With Poor Prognosis and Promotes Metastasis Through PI3K/AKT Pathway in Colorectal Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Zongxia Wang ◽  
Lizhou Jia ◽  
Yushu sun ◽  
Chunli Li ◽  
Lingli Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Poor Prognosis ◽  
Akt Signaling ◽  
Actin Binding ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Related Proteins

Trophoblast cell surface protein 2 (Trop2) is one of the cancer-related proteins that plays a vital role in biological aggressiveness and poor prognosis of colorectal cancer (CRC). The study of the Trop2 related network is helpful for us to understand the mechanism of tumorigenesis. However, the effects of the related proteins interacting with Trop2 in CRC remain unclear. Here, we found that coronin-like actin-binding protein 1C (CORO1C) could interact with Trop2 and the expression of CORO1C in CRC tissues was higher than that in paracarcinoma tissues. The expression of CORO1C was associated with histological type, lymph node metastasis, distant metastasis, AJCC stage, venous invasion, and perineural invasion. The correlation between CORO1C expression and clinical characteristics was analyzed demonstrating that high CORO1C expression in CRC patients were associated with poor prognosis. Furthermore, CORO1C knockdown could decrease the cell proliferation, colony formation, migration and invasion in vitro and tumor growth in vivo. The underlying mechanisms were predicted by bioinformatics analysis and verified by Western blotting. We found that PI3K/AKT signaling pathway was significantly inhibited by CORO1C knockdown and the tuomr-promoting role of CORO1C was leastwise partly mediated by PI3K/AKT signaling pathway. Thus, CORO1C may be a valuable prognostic biomarker and drug target in CRC patients.

scholarly journals Targeting ERK induced cell death and p53/ROS-dependent protective autophagy in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wunan Mi ◽  
Chuyue Wang ◽  
Guang Luo ◽  
Jiehan Li ◽  
Yizheng Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Vital Role ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Treatment Groups ◽  
Combinational Treatment

AbstractIn recent years, many studies have shown that autophagy plays a vital role in the resistance of tumor chemotherapy. However, the interaction between autophagy and cell death has not yet been clarified. In this study, a new specific ERK inhibitor CC90003 was found to suppress colorectal cancer growth by inducing cell death both in vitro and in vivo. Studies have confirmed that higher concentrations of ROS leads to autophagy or cell death. In this research, the role of CC90003-induced ROS was verified. But after inhibiting ROS by two kinds of ROS inhibitors NAC and SFN, the autophagy induced by CC90003 decreased, while cell death strengthened. In parallel, protective autophagy was also induced, while in a p53-dependent manner. After silencing p53 or using the p53 inhibitor PFTα, the autophagy induced by CC90003 was weakened and the rate of cell death increases. Therefore, we confirmed that CC90003 could induce autophagy by activating ROS/p53. Furthermore, in the xenograft mouse model, the effect was obtained remarkably in the combinational treatment group of CC90003 plus CQ, comparing with that of the single treatment groups. In a word, our results demonstrated that targeting ERK leads to cell death and p53/ROS-dependent protective autophagy simultaneously in colorectal cancer, which offers new potential targets for clinical therapy.

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