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Expanding CYLD protein in NF-κβ/TNF-α signaling pathway in response to Lactobacillus acidophilus in non-metastatic rectal cancer patients.

  • 2023-09-19
  • Medical oncology (Northwood, London, England) 40(10)
    • Farhad Zamani
    • Solmaz Khalighfard
    • Mohammad Reza Kalhori
    • Amirhoushang Poorkhani
    • Taghi Amiriani
    • Payam Hosseinzadeh
    • Ebrahim Esmati
    • Mahdi Alemrajabi
    • Alireza Nikoofar
    • Fahimeh Safarnezhad Tameshkel
    • Ali Mohammad Alizadeh

Study Design

Type
Randomized Controlled Trial (RCT)
Population
110 patients with non-metastatic rectal cancer
Methods
Randomized placebo-controlled, L. acidophilus probiotic (500 mg, three times daily) and placebo groups for 13 weeks, evaluation using ELISA and qPCR, survival measured after five years
Duration
13 weeks
Funding
Unclear
The CYLD gene is a tumor suppressor, reduced in many cancers. Here, we aimed to investigate CYLD protein level and NF-κβ/TNF-α signaling pathway in rectal cancer patients with Lactobacillus acidophilus (L. acidophilus) consumption. One hundred ten patients with non-metastatic rectal cancer were randomly divided into L. acidophilus probiotic (500 mg, three times daily) and placebo groups for 13 weeks. The expression of CYLD, TNF-α, and NF-κB proteins and the genes involved in the NF-κβ/TNF-α pathway were evaluated using ELISA and qPCR techniques. The survival rate was measured after five years. Unlike the placebo group, the results showed a significant increase in the expression of CYLD protein and tumor suppressor genes, including FOXP3, ROR-γ, Caspase3, GATA3, T-bet, and a considerable decrease in the expression of NF-ҝβ and TNF-α proteins and oncogenes, including STAT3, 4, 5, 6, and SMAD 3, in the probiotic group. A higher overall survival rate was seen after L. acidophilus consumption compared to the placebo group (P < 0.05). L. acidophilus consumption can reduce inflammation factors by affecting CYLD protein and its downstream signaling pathways. A schematic plot of probiotic consumption Effects on the CYLD protein in regulating the NF-ĸβ signaling pathway in colorectal cancer. NF-ĸβ can be activated by canonical and noncanonical pathways, which rely on IκB degradation and p100 processing, respectively. In the canonical NF-κβ pathway, dimmers, such as p65/p50, are maintained in the cytoplasm by interacting with an IκBα protein. The binding of a ligand to a cell-surface receptor activates TRAF2, which triggers an IKK complex, containing -α, -β, -g, which phosphorylates IKK-β. It then phosphorylates IκB-α, leading to K48-ubiquitination and degradation of this protein. The p65/p50 protein freely enters the nucleus to turn on target genes. The non-canonical pathway is primarily involved in p100/RelB activation. It differs from the classical pathway in that only certain receptor signals activate this pathway. It proceeds through an IKK complex that contains two IKK-α subunits but not NEMO. Several materials including peptidoglycan, phorbol, myristate, acetate, and gram-positive bacteria such as probiotics inhibit NF-κB by inducing CYLD. This protein can block the canonical and noncanonical NF-κβ pathways by removing Lys-63 ubiquitinated chains from activated TRAFs, RIP, NEMO, and IKK (α, β, and γ). Moreover, TNF-α induces apoptosis by binding caspase-3 to FADD.

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