Transcriptional modulation of SLC26A3 (DRA) by sphingosine-1-phosphate

Anbazhagan, Arivarasu Natarajan; Priyamvada, Shubha; Alakkam, Anas; Kumar, Anoop; Borthakur, Alip; Saksena, Seema; Gill, Ravinder K.; Alrefai, Waddah A.; Dudeja, Pradeep K.

doi:10.1152/ajpgi.00308.2015

Cited by 8 publications

(4 citation statements)

References 47 publications

(69 reference statements)

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“…However, Di Stadio et al reported that SLC26A3 acts on the MAP kinases pathway to maintain mucosal integrity and prevent gastric cancer [ 34 ]. Furthermore, the expression of the SLC26A3 gene may be influenced by the PI3K/AKT pathway in the mammalian intestine [ 35 , 36 ]. Hence, to elucidate the molecular mechanism of SLC26A3 in CRC progression, we overexpressed the SLC26A3 gene in colorectal cancer cell lines and performed RNA sequencing on cells with SLC26A3 overexpression.…”

Section: Discussionmentioning

confidence: 99%

SLC26A3/NHERF2-IκB/NFκB/p65 feedback loop suppresses tumorigenesis and metastasis in colorectal cancer

Lin,

Lin

et al. 2023

Oncogenesis

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Colorectal cancer (CRC) is a formidable disease due to the intricate mechanisms that drive its proliferation and metastasis. Despite significant progress in cancer research, the integration of these mechanisms that influence cancer cell behavior remains elusive. Therefore, it is imperative to comprehensively elucidate the underlying mechanisms driving CRC proliferation and metastasis. In this study, we reported a novel role of SLC26A3 in suppressing CRC progression. We found that SLC26A3 expression was downregulated in CRC, which was proportionally correlated with survival. Our in vivo and in vitro experiments demonstrated that up-regulation of SLC26A3 inhibited CRC proliferation and metastasis, while down-regulation of SLC26A3 promoted CRC progression by modulating the expression level of IκB. Furthermore, we identified NHERF2 as a novel interacting protein of SLC26A3 responsible for stabilizing the IκB protein and removing ubiquitination modification. Mechanistically, SLC26A3 augmented the interaction between NHERF2 and IκB, subsequently reducing its degradation. This process inhibited the dissociation of p65 from the IκB/p65/p50 complex and reduced the translocation of p65 from the cytoplasm to the nucleus. Moreover, our investigation revealed that NF-κB/p65 directly bound to the promoter of SLC26A3, leading to a decline in its mRNA expression. Thus, SLC26A3 impeded the nuclear translocation of NF-κB/p65, enhancing the transcription of SLC26A3 and establishing a positive regulatory feedback loop in CRC cells. Collectively, these results suggest that a SLC26A3/NHERF2-IκB/NF-κB/p65 signaling loop suppresses proliferation and metastasis in CRC cells. These findings propose a novel SLC26A3-driven signaling loop that regulates proliferation and metastasis in CRC, providing promising therapeutic interventions and prognostic targets for the management of CRC.

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Section: Discussionmentioning

confidence: 99%

SLC26A3/NHERF2-IκB/NFκB/p65 feedback loop suppresses tumorigenesis and metastasis in colorectal cancer

Lin,

Lin

et al. 2023

Oncogenesis

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“…The complex interactions of sphingolipids with nuclear gene regulation suggest close links between these pathways, but detailed understanding is missing. The ability of the sphingosine mimetic drug FTY720/fingolimod to modulate gene expression in neurons and astrocytes [38, 39] is probably due in large part to the links observed between S1P receptor signaling and the activities of crucial transcription factors including NF-κB, Yin-Yang-1, or Notch [71–75]. However, the inhibition of class I HDACs by FTY720 / FTY720P must also be considered a potential mechanism [41, 42].…”

Section: Discussionmentioning

confidence: 99%

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

et al. 2018

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Sphingolipid signaling disturbances correlate with Alzheimer's disease (AD) progression. We examined the influence of FTY720/fingolimod, a sphingosine analog and sphingosine-1-phosphate (S1P) receptor modulator, on the expression of sphingolipid metabolism and signaling genes in a mouse transgenic AD model. Our results demonstrated that AβPP (V717I) transgene led with age to reduced mRNA expression of S1P receptors (S1PRs), sphingosine kinase SPHK2, ceramide kinase CERK, and the anti-apoptotic Bcl2 in the cerebral cortex and hippocampus, suggesting a pro-apoptotic shift in 12-month old mice. These changes largely emulated alterations we observed in the human sporadic AD hippocampus: reduced SPHK1, SPHK2, CERK, S1PR1, and BCL2. We observed that the responses to FTY720 treatment were modified by age and notably differed between control (APP − ) and AD transgenic (APP + ) animals. AβPP (V717I)-expressing 12-month-old animals reacted to fingolimod with wide changes in the gene expression program in cortex and hippocampus, including increased pro-survival SPHKs and CERK. Moreover, BCL2 was elevated by FTY720 in the cortex at all ages (3, 6, 12 months) while in hippocampus this increase was observed at 12 months only. In APP − mice, fingolimod did not induce any significant mRNA changes at 12 months. Our results indicate significant effect of FTY720 on the age-dependent transcription of genes involved in sphingolipid metabolism and pro-survival signaling, suggesting its neuroprotective role in AD animal model.

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“…This is achieved through S1P-mediated activation of ERK1/2 via S1PR2 [43]. Furthermore, S1P-mediated activation of S1PR2 leads to increased expression of down-regulated in adenoma (DRA), the major Cl-/HCO3-exchanger that regulates NaCl absorption in the intestine of mammals [54]. MEK/ERK activity controls JNK activation via regulating MAPK phosphatase (MKP-1), which prevents cell apoptosis.…”

Section: Implication In Intestinal Barrier Homeostasismentioning

confidence: 99%

Signaling through the S1P−S1PR Axis in the Gut, the Immune and the Central Nervous System in Multiple Sclerosis: Implication for Pathogenesis and Treatment

Chatzikonstantinou

Poulidou

Arnaoutoglou

et al. 2021

Cells

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Sphingosine 1-phosphate (S1P) is a signaling molecule with complex biological functions that are exerted through the activation of sphingosine 1-phosphate receptors 1–5 (S1PR1–5). S1PR expression is necessary for cell proliferation, angiogenesis, neurogenesis and, importantly, for the egress of lymphocytes from secondary lymphoid organs. Since the inflammatory process is a key element of immune-mediated diseases, including multiple sclerosis (MS), S1PR modulators are currently used to ameliorate systemic immune responses. The ubiquitous expression of S1PRs by immune, intestinal and neural cells has significant implications for the regulation of the gut–brain axis. The dysfunction of this bidirectional communication system may be a significant factor contributing to MS pathogenesis, since an impaired intestinal barrier could lead to interaction between immune cells and microbiota with a potential to initiate abnormal local and systemic immune responses towards the central nervous system (CNS). It appears that the secondary mechanisms of S1PR modulators affecting the gut immune system, the intestinal barrier and directly the CNS, are coordinated to promote therapeutic effects. The scope of this review is to focus on S1P−S1PR functions in the cells of the CNS, the gut and the immune system with particular emphasis on the immunologic effects of S1PR modulation and its implication in MS.

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Transcriptional modulation of SLC26A3 (DRA) by sphingosine-1-phosphate

Abstract: . Transcriptional modulation of SLC26A3 (DRA) by sphingosine-1-phosphate.

Cited by 8 publications

References 47 publications

SLC26A3/NHERF2-IκB/NFκB/p65 feedback loop suppresses tumorigenesis and metastasis in colorectal cancer

SLC26A3/NHERF2-IκB/NFκB/p65 feedback loop suppresses tumorigenesis and metastasis in colorectal cancer

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

Signaling through the S1P−S1PR Axis in the Gut, the Immune and the Central Nervous System in Multiple Sclerosis: Implication for Pathogenesis and Treatment

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