ArticleJournal of experimental & clinical cancer research : CR2022
ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer.
Article in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 266 papers.
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Who cites it
266 citing papers in PubMed, 421 citations in OpenAlex.
- Metabolic reprogramming in colorectal cancer: Mechanisms and therapeutic insights.Genes & diseases · 2027Review
- Mep1a Knockout Attenuates Unilateral Ureteral Obstruction-Induced Renal Injury by Inhibiting Glycolysis.Current medical science · 2026Article
- Beyond the Monolayer: Leveraging 3D Culture Systems to Decode Mechanisms of Drug Resistance and Therapeutic Vulnerabilities in Colorectal Cancer.Cancer medicine · 2026Review
- Review
- PI3K/AKT signaling pathway: molecular crossroads in tumorigenesis and therapeutic innovation.Signal transduction and targeted therapy · 2026Review
- Hypoxia-inducible factor-1α promotes the malignant progression of cervical cancer cells by regulating lactate dehydrogenase A-mediated glycolysis.Translational cancer research · 2026Article
- Targeting RPRD1B overcomes chemoresistance in gastric cancer by suppressing the TOPBP1-mediated DNA damage repair pathway.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- HIFs: The central drivers of tumors and their role as molecular switches in targeted therapy?Acta pharmaceutica Sinica. B · 2026Review
- Mechanically Regulated Nanozymes for Remote Metabolic Reprogramming and Precise Cancer Therapy.Angewandte Chemie (International ed. in English) · 2026Article
- Cascade-responsive HA-decorated liposome/mesoporous silica nanoplatform co-delivering BMF-219 and 5-FU enhances gastric cancer chemotherapy through Menin- and p53-associated apoptotic signaling.Journal of experimental & clinical cancer research : CR · 2026Article
- Targeting m6A-SCG2-TAMs axis overcomes 5-FU resistance in colorectal cancer via a multi-omics model.NPJ digital medicine · 2026Article
- Combination of ivermectin and metformin promotes autophagy in MCF‑7 cells by inhibiting phosphorylation of the PI3K/AKT/mTOR pathway.Oncology reports · 2026Article
- The Serpin Superfamily in Adipose Tissue Remodeling: Molecular Drivers of Immune-Metabolic Crosstalk and Insulin Sensitivity.Biology · 2026Review
- Sulconazole Suppresses Colorectal Cancer Immune Evasion by Inhibiting Glycolysis to Upregulate OVOL2 PARylation and Induce PANoptosis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Review
- Whole genome sequencing of pre-treatment and post-treatment locally advanced rectal cancer using long and short read technologies.Scientific reports · 2026Article
- Tumor microenvironment-responsive ARRDC4: unveiling the tumor-suppressive pathway in colorectal cancer progression.Cancer cell international · 2026Article
- PTBP1 is upregulated in response to Zika virus infection and restrains viral replication by hijacking viral NS1 protein to induce NS1 degradation.Journal of virology · 2026Article
- B3GNT6 suppresses colorectal cancer progression by inhibiting the KRAS/ERK signaling pathway.BMC biotechnology · 2026Article
- A RIG-I targeting nanozyme induces PANoptosis for cancer immunotherapy.Nature communications · 2026Article
206 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundAcquired resistance of 5-fluorouracil (5-FU) remains a clinical challenge in colorectal cancer (CRC), and efforts to develop targeted agents to reduce resistance have not yielded success. Metabolic reprogramming is a key cancer hallmark and confers several tumor phenotypes including chemoresistance. Glucose metabolic reprogramming events of 5-FU resistance in CRC has not been evaluated, and whether abnormal glucose metabolism could impart 5-FU resistance in CRC is also poorly defined.
methodsThree separate acquired 5-FU resistance CRC cell line models were generated, and glucose metabolism was assessed by measuring glucose and lactate utilization, RNA and protein expressions of glucose metabolism-related enzymes and changes of intermediate metabolites of glucose metabolite pool. The protein levels of hypoxia inducible factor 1α (HIF-1α) in primary tumors and circulating tumor cells of CRC patients were detected by immunohistochemistry and immunofluorescence. Stable HIF1A knockdown in cell models was established with a lentiviral system. The influence of both HIF1A gene knockdown and pharmacological inhibition on 5-FU resistance in CRC was evaluated in cell models in vivo and in vitro.
resultsThe abnormality of glucose metabolism in 5-FU-resistant CRC were described in detail. The enhanced glycolysis and pentose phosphate pathway in CRC were associated with increased HIF-1α expression. HIF-1α-induced glucose metabolic reprogramming imparted 5-FU resistance in CRC. HIF-1α showed enhanced expression in 5-FU-resistant CRC cell lines and clinical specimens, and increased HIF-1α levels were associated with failure of fluorouracil analog-based chemotherapy in CRC patients and poor survival. Upregulation of HIF-1α in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of β-catenin in the nucleus. Both HIF-1α gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU.
conclusionsHIF-1α is a potential biomarker for 5-FU-resistant CRC, and targeting HIF-1a in combination with 5-FU may represent an effective therapeutic strategy in 5-FU-resistant CRC.
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