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 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 Disulfiram/Copper Complex Induces Autophagic Cell Death in Colorectal Cancer by Targeting ULK1

2021 ◽  
Vol 12 ◽  
Author(s):  
Yeting Hu ◽  
Yucheng Qian ◽  
Jingsun Wei ◽  
Tian Jin ◽  
Xiangxing Kong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Therapeutic Strategy ◽  
Whole Genome ◽  
Library Screening ◽  
Inhibit Tumor Growth ◽  
Squamous Cells ◽  
Novel Therapeutic

Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.

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 N-myc downstream-regulated gene 1 inhibits the proliferation of colorectal cancer through emulative antagonizing NEDD4-mediated ubiquitylation of p21

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Sen Zhang ◽  
Chaoran Yu ◽  
Xiao Yang ◽  
Hiju Hong ◽  
Jiaoyang Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Metastasis ◽  
Patient Survival ◽  
Xenograft Model ◽  
Cancer Tissue ◽  
Tumor Proliferation ◽  
Human Colorectal Cancer ◽  
Ubiquitylation Assay

Abstract Background N-myc downstream-regulated gene 1 (NDRG1) has been shown to play a key role in tumor metastasis. Recent studies demonstrate that NDRG1 can suppress tumor growth and is related to tumor proliferation; however, the mechanisms underlying these effects remain obscure. Methods Immunohistochemistry (IHC) was used to detect NDRG1 and p21 protein expression in colorectal cancer tissue, and clinical significance of NDRG1 was also analyzed. CCK-8 assay, colony formation assay, flow cytometry, and xenograft model were used to assess the effect of NDRG1 on tumor proliferation in vivo and in vitro. The mechanisms underlying the effect of NDRG1 were investigated using western blotting, immunofluorescence, immunoprecipitation, and ubiquitylation assay. Results NDRG1 was down-regulated in CRC tissues and correlated with tumor size and patient survival. NDRG1 inhibited tumor proliferation through increasing p21 expression via suppressing p21 ubiquitylation. NDRG1 and p21 had a positive correlation both in vivo and in vitro. Mechanistically, E3 ligase NEDD4 could directly interact with and target p21 for degradation. Moreover, NDRG1 could emulatively antagonize NEDD4-mediated ubiquitylation of p21, increasing p21 expression and inhibit tumor proliferation. Conclusion Our study could fulfill potential mechanisms of the NDRG1 during tumorigenesis and metastasis, which may serve as a tumor suppressor and potential target for new therapies in human colorectal cancer.

Efficacy of vemurafenib, a selective BRAFV600E inhibitor, in combination with a MEK inhibitor in BRAFV600E colorectal cancer models.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 488-488 ◽  
Author(s):  
Brian Higgins ◽  
Kenneth Daniel Kolinsky ◽  
Hong Yang ◽  
Min Jung Kim ◽  
Jia Kui Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Apoptosis Induction ◽  
Braf Mutations ◽  
Xenograft Models ◽  
Pathway Inhibition ◽  
Anti Tumor Activity

488 Background: BRAF mutations occur in about 10% of colorectal cancer (CRC). Most BRAF mutations involve the V600E amino acid substitution, resulting in constitutive activation of the MAPK signaling pathway. Vemurafenib (RG7204, PLX4032) is a first-in-class, BRAFV600E-specific small molecule inhibitor that dose-dependently inhibits tumor growth in V600E CRC xenografts. However, unlike responses observed in melanoma, single agent vemurafenib in a Phase I extension trial of 20 patients with previously treated metastatic CRC, resulted in only 5% response rate. The goal here was to explore in vitro and in vivo if addition of a MEK inhibitor (MEKi) could increase effects of vemurafenib on anti-proliferation and anti-tumor activity in BRAFV600E CRC cell lines. Methods: Combo of vemurafenib with a MEKi was tested in MTT assay for antiproliferative effect and combination effect was determined by combination index (CI) calculated by the CalcySyn software. Western analysis and Annexin V staining were utilized to evaluate combo effects on pathway inhibition and apoptosis induction. Optimal doses of both vemurafenib and MEKi were tested as single agent and in combination in the Colo205 and LS411N CRC xenograft models in nude mice. Results: Synergistic anti-proliferative effect was observed with the combo of vemurafenib and a MEKi in the V600E positive CRC cell lines tested. More effective pathway inhibition and apoptosis induction were observed with combo than either agent alone. Combination of vemurafenib and a MEKi delivered greater anti-tumor activity and increased life span of animals in the Colo205 and LS411N CRC xenograft models. Conclusions: These in vitro and in vivo data suggest that combined pharmacologic blockade within the RAS/RAF/MEK/ERK pathway is more effective than either agent alone and may be a way to exploit greater antitumor activity CRC patients in clinic.

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