Review of 5-FU resistance mechanisms in colorectal cancer: clinical significance of attenuated on-target effects

Gmeiner, William H.; Okechukwu, Charles Chidi

doi:10.20517/cdr.2022.136

Cited by 13 publications

(9 citation statements)

References 132 publications

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“…5-FU, an early-reported chemotherapeutic drug, remains a cornerstone in the systemic treatment of CRC. Despite advancements in cancer treatment, the prognosis of CRC patients receiving 5-FU therapy remains unsatisfactory [ 32 ]. Therefore, it is crucial to explore and enhance the sensitivity of 5-FU to better design appropriate treatment strategies and achieve personalized care that effectively improves patient outcomes.…”

Section: Discussionmentioning

confidence: 99%

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB

Liu,

Zhang,

et al. 2024

Cell Commun Signal

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Background While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood. Methods We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses. Results Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy. Conclusions Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.

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Section: Discussionmentioning

confidence: 99%

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB

Liu,

Zhang,

et al. 2024

Cell Commun Signal

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“…Given the important toxicity of these treatments, identifying those patients is very important in order to improve their quality of life and prevent their exposure to a medication with limited interest and high toxicity for them. We found that one of the genes most associated and predictive of the CIMP phenotype is TYMS (thymidylate synthase), which has been shown to be up-regulated by Myc [ 41 ] and to drive resistance to 5-FU treatments, although it is the target of the drug [ 42 , 43 ]. Hence, since the 1C-metabolism pathway seems to play a central role in CIMP tumours, other targets in the pathway should be explored.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylated Colorectal Cancer Tumours Present a Myc-Driven Hypermetabolism with a One-Carbon Signature Associated with Worsen Prognosis

Desterke,

Jaulin,

Dornier

2024

Biomedicines

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Colorectal cancer (CRC) is the second cause of cancer-related death; the CpG-island methylation pathway (CIMP) is associated with KRAS/BRAF mutations, two oncogenes rewiring cell metabolism, worse prognosis, and resistance to classical chemotherapies. Despite this, the question of a possible metabolic rewiring in CIMPs has never been investigated. Here, we analyse whether metabolic dysregulations are associated with tumour methylation by evaluating the transcriptome of CRC tumours. CIMP-high patients were found to present a hypermetabolism, activating mainly carbohydrates, folates, sphingolipids, and arachidonic acid metabolic pathways. A third of these genes had epigenetic targets of Myc in their proximal promoter, activating carboxylic acid, tetrahydrofolate interconversion, nucleobase, and oxoacid metabolisms. In the Myc signature, the expression of GAPDH, TYMS, DHFR, and TK1 was enough to predict methylation levels, microsatellite instability (MSI), and mutations in the mismatch repair (MMR) machinery, which are strong indicators of responsiveness to immunotherapies. Finally, we discovered that CIMP tumours harboured an increase in genes involved in the one-carbon metabolism, a pathway critical to providing nucleotides for cancer growth and methyl donors for DNA methylation, which is associated with worse prognosis and tumour hypermethylation. Transcriptomics could hence become a tool to help clinicians stratify their patients better.

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“…Resistance is estimated to occur in 90% of metastatic CRC cases [124]. The possible mechanisms of resistance to 5-FU are complex and varied and have been described extensively in the literature [124][125][126]. The most common are changes in the expression of genes encoding enzymes involved in the metabolism of 5-FU, particularly the upregulation of thymidylate synthase, the main enzyme [127].…”

Section: Simultaneous Stimulation With Thymoquinone and Known Chemoth...mentioning

confidence: 99%

Thymoquinone: A Promising Therapeutic Agent for the Treatment of Colorectal Cancer

Kurowska,

Madej,

Strzalka-Mrozik

2023

CIMB

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and is responsible for approximately one million deaths each year. The current standard of care is surgical resection of the lesion and chemotherapy with 5-fluorouracil (5-FU). However, of concern is the increasing incidence in an increasingly younger patient population and the ability of CRC cells to develop resistance to 5-FU. In this review, we discuss the effects of thymoquinone (TQ), one of the main bioactive components of Nigella sativa seeds, on CRC, with a particular focus on the use of TQ in combination therapy with other chemotherapeutic agents. TQ exhibits anti-CRC activity by inducing a proapoptotic effect and inhibiting proliferation, primarily through its effect on the regulation of signaling pathways crucial for tumor progression and oxidative stress. TQ can be used synergistically with chemotherapeutic agents to enhance their anticancer effects and to influence the expression of signaling pathways and other genes important in cancer development. These data appear to be most relevant for co-treatment with 5-FU. We believe that TQ is a suitable candidate for consideration in the chemoprevention and adjuvant therapy for CRC, but further studies, including clinical trials, are needed to confirm its safety and efficacy in the treatment of cancer.

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Review of 5-FU resistance mechanisms in colorectal cancer: clinical significance of attenuated on-target effects

Cited by 13 publications

References 132 publications

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB

Hypermethylated Colorectal Cancer Tumours Present a Myc-Driven Hypermetabolism with a One-Carbon Signature Associated with Worsen Prognosis

Thymoquinone: A Promising Therapeutic Agent for the Treatment of Colorectal Cancer

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