The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy.
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ABSTRACT:
SUBMITTER: Chen J
PROVIDER: S-EPMC8195740 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAs EIF3D is oncogenic in colorectal cancer (CRC) and is associated with multidrug resistance, this study aims to investigate whether and how EIF3D regulates resistance to 5-fluorouracil (5-Fu) in CRC.MethodsEIF3D-associated genes in CRC were predicted using bioinformatics tools. CRC cells and nude mice received 5-Fu treatment. Then, the impacts of EIF3D and the interaction between EIF3D and RUVBL1 on cell viability, colony formation, apoptosis, and DNA damage were detected through MTT, colony formation, flow cytometry, and immunofluorescence assays, and those on in vivo tumorigenesis through murine xenograft assay. IC50 value of 5-Fu for CRC cells was determined by probit regression analysis. Expressions of EIF3D, eIF4E, EIF3D-associated genes, γH2AX, Bcl-2, Bax, and Cleaved Caspase-3/Caspase-3 in CRC tissues, cells, and/or xenograft tumors were analyzed by qRT-PCR and/or Western blot.ResultsEIF3D and RUVBL1 were highly expressed and positively correlated with CRC tissues/cells. In CRC cells, except for eIF4E, both EIF3D and RUVBL1 levels were upregulated by 5-Fu treatment; in addition to that, RUVBL1 level was downregulated by EIF3D silencing rather than eIF4E. Meanwhile, EIF3D silencing diminished IC50 value of 5-Fu and potentiated 5-Fu-induced viability decrease, colony formation inhibition, apoptosis promotion, Bcl-2 downregulation, and γH2AX, Bax, and Cleaved Caspase-3/Caspase-3 upregulation but reversed 5-Fu-triggered RUVBL1 upregulation. RUVBL1 overexpression offsets EIF3D silencing-induced viability decrease and apoptosis promotion of 5-Fu-treated CRC cells, and tumorigenesis suppression and apoptosis promotion in 5-Fu-treated mice.ConclusionEIF3D promotes resistance to 5-Fu in CRC through upregulating RUVBL1 level.
| S-EPMC9937894 | biostudies-literature
Project description:To cope with intrinsic and environmental stress, cancer cells rely on adaptive pathways more than non-transformed counterparts. Such non-oncogene addiction offers new therapeutic targets and strategies to overcome chemoresistance. In an attempt to study the role of adaptive pathways in acquired drug resistance in carcinoma cells, we devised a model of in vitro conditioning to three standard chemotherapeutic agents, cisplatin, 5-fluorouracil, and docetaxel, from the epithelial cancer cell line, HEp-2, and investigated the mechanisms underlying reduced drug sensitivity. We found that triple-resistant cells suffered from higher levels of oxidative stress, and showed heightened anti-stress responses, including the antioxidant Nrf2 pathway and autophagy, a conserved pleiotropic homeostatic strategy, mediating the clearance of aggregates marked by the adapter p62/SQSTM1. As a result, re-administration of chemotherapeutic agents failed to induce further accumulation of reactive oxygen species and p62. Moreover, autophagy proved responsible for chemoresistance through the avoidance of p62 accumulation into toxic protein aggregates. Indeed, p62 ablation was sufficient to confer resistance in parental cells, and genetic and pharmacological autophagic inhibition restored drug sensitivity in resistant cells in a p62-dependent manner. Finally, exogenous expression of mutant p62 lacking the ubiquitin- and LC3-binding domains, required for autophagic engulfment, increased chemosensitivity in TDR HEp-2 cells. Altogether, these findings offer a cellular system to investigate the bases of acquired chemoresistance of epithelial cancers and encourage challenging the prognostic and antineoplastic therapeutic potential of p62 toxicity.
| S-EPMC6070274 | biostudies-literature
Project description:Drug resistance is one of the main hurdles to overcome for the improvement of cancer patient survival. However, the underlying mechanisms remain largely unknown, and therapeutic options are limited. Here, we demonstrate a strong correlation between HMGA2 expression and chemosensitivity to 5-fluorouracil (5-FU), a widely used first-line systemic chemotherapy regimen for colorectal cancer (CRC) patients. Overexpression of HMGA2 enhances chemoresistance to 5-FU of CRC both in vitro and in vivo. Further experiments indicate that HMGA2 directly binds to the promoter of Dvl2 and induces its transcription, which leads to increased activation of the Wnt/?-catenin pathway. Taken together, our data suggest that HMGA2 enhances the chemoresistance to 5-FU in CRC via activating the Dvl2/Wnt pathway. Therefore, HMGA2 may serve as a predictive biomarker and a potential therapeutic target in CRC.
| S-EPMC5839414 | biostudies-literature
Project description:Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC.
| S-EPMC6795411 | biostudies-literature
Project description:Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.
| S-EPMC5767127 | biostudies-literature
Project description:Chemotherapy is a common strategy to treat cancer. However, acquired resistance and metastasis are the major obstacles to successful treatment. Anastasis is a process by which cells survive executioner caspase activation when facing apoptotic stress. Here we demonstrate that colorectal cancer cells can undergo anastasis after transient exposure to chemotherapeutic drugs. Using a lineage tracing system to label and isolate cells that have experienced executioner caspase activation in response to drug treatment, we show that anastasis grants colorectal cancer cells enhanced migration, metastasis, and chemoresistance. Mechanistically, treatment with chemotherapeutic drugs induces upregulated expression of cIAP2 and activation of NFκB, which are required for cells to survive executioner caspase activation. The elevated cIAP2/NFκB signaling persists in anastatic cancer cells to promote migration and chemoresistance. Our study unveils that cIAP2/NFκB-dependent anastasis promotes acquired resistance and metastasis after chemotherapy.
| S-EPMC10313691 | biostudies-literature
Project description:BackgroundEmerging evidence suggests a potential relationship between gut microbiota and the host response to chemotherapeutic drugs including 5-fluorouracil (5-Fu). Fusobacterium nucleatum (Fn) has been linked to the initiation and progression of colorectal cancer (CRC). Unfortunately, little was known about the relationship between Fn infection and chemotherapeutic efficacy. Here, we investigate the potential relationship between Fn infection and chemotherapeutic efficacy of 5-Fu in CRC.MethodsDifferentially expressed genes of CRC cell lines induced by Fn infection were analyzed based on a whole genome microarray analysis Then, we explored the relationship between upregulation of BIRC3 induced by Fn infection and chemoresistance to 5-Fu in vitro and in vivo. Furthermore, we dissected the mechanisms involved in Fn-induced BIRC3 expression. Finally, we investigated the clinical relevance of Fn infection, BIRC3 protein expression and chemoresistance to 5-Fu treatment in CRC patients.ResultsBIRC3 was the most upregulated gene induced by Fn infection via the TLR4/NF-?B pathway in CRC cells; Fn infection reduced the chemosensitivity of CRC cells to 5-Fu through upregulation of BIRC3 in vitro and in vivo. High Fn abundance correlated with chemoresistance in advanced CRC patients who received standard 5-Fu-based adjuvant chemotherapy after radical surgery.ConclusionsOur evidence suggests that Fn and BIRC3 may serve as promising therapeutic targets for reducing chemoresistance to 5-Fu treatment in advanced CRC.
| S-EPMC6327560 | biostudies-literature
Project description:Chemoresistance against 5-fluorouracil (5-FU) is a major issue for colorectal cancer (CRC) patients. Increasing evidence for the roles of CD147 in glycolipid metabolic reprogramming and chemoresistance of tumor cells has emerged in recent years. However, whether CD147 contributes to 5-FU resistance in CRC and the role of abnormal glycolipid metabolism in this process remain poorly understood. We analyzed CD147 expression in primary tumor samples of CRC patients and found that upregulated CD147 correlated with decreased 5-FU chemosensitivity and an unfavorable prognosis of CRC patients. Moreover, in vivo and in vitro experiments confirmed that CD147 regulates glycolipid metabolism through two separate pathways. Mechanistically, CD147 upregulates HIF-1α-mediated glycolysis by activating the PI3K/AKT/mTOR pathway and CD147 also attenuates PPARα-mediated fatty acid oxidation by activation of the MAPK pathway. Most importantly, we found that CD147 confers 5-FU resistance in CRC via these glycolipid metabolic signatures. Our results demonstrated that CD147 is a potential 5-FU resistance biomarker for CRC patients and a candidate therapeutic target to restore 5-FU sensitivity of 5-FU-resistant CRC by remodeling glycolipid metabolism.
| S-EPMC9309564 | biostudies-literature
Project description:PurposeCancer-associated fibroblasts (CAFs) activated by cancer cells has a central role in development and malignant biological behavior in colorectal cancer (CRC). Adult fibroblasts do not express Snail, but Snail-positive fibroblasts are discovered in the stroma of malignant CRC and reported to be the key role to chemoresistance. However, the reciprocal effect of CAFs expressed Snail to chemoresistance on CRC cells and the underlying molecular mechanisms are not fully characterized.Materials and methodsSnail-overexpressed 3T3 stable cell lines were generated by lipidosome and CT26 mixed with 3T3-Snail subcutaneous transplanted CRC models were established by subcutaneous injection. Cell Counting Kit-8, flow cytometry and western blotting assays were performed, and immunohistochemistry staining was studied. The cytokines participated in chemoresistance was validated with reverse transcriptase-polymerase chain reaction and heatmap.ResultsSnail-expression fibroblasts are discovered in human and mouse spontaneous CRCs. Overexpression of Snail induces 3T3 fibroblasts transdifferentiation to CAFs. CT26 co-cultured with 3T3-Snail resisted the impairment from 5-fluorouracil and paclitaxel in vitro. The subcutaneous transplanted tumor models included 3T3-Snail cells develop without restrictions even after treating with 5-fluorouracil or paclitaxel. Moreover, these chemoresistant processes may be mediated by CCL1 secreted by Snail-expression fibroblasts via transforming growth factor β/nuclear factor-κB signaling pathways.ConclusionTaken together, Snail-expressing 3T3 fibroblasts display CAFs properties that support 5-fluorouracil and paclitaxel chemoresistance in CRC via participation of CCL1 and suggest that inhibition of the Snail-expression fibroblasts in tumor may be a useful strategy to limit chemoresistance.
| S-EPMC6056976 | biostudies-literature
Project description:PurposeSMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance.ResultsThe discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival.ConclusionsOur data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.
| S-EPMC6421131 | biostudies-literature