Free-Fatty Acid Receptor-4 (FFA4/GPR120) differentially regulates migration, invasion, proliferation and tumor growth of papillary renal cell carcinoma cells

Karmokar, Priyanka F.; Moniri, Nader H.

doi:10.1016/j.bcp.2023.115590

Cited by 4 publications

(5 citation statements)

References 69 publications

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“…2 B). Interestingly, the effects seen with this agonist were higher than that seen with GW9508, suggesting that removal of the FFA4-acting component facilitates greater proliferation, consistent with our recent report that FFA4 agonism inhibits cell proliferation [ 15 ]. As seen with GW9508, GW1100 completely inhibited the effects of AS2034178 at days 5 and 6 of growth ( p < 0.0001; d = 4.1 and p < 0.0001; d = 3.1 versus AS2034178, respectively), and GW1100 alone also significantly inhibited cell proliferation at days 5 and 6 ( p < 0.001; d = 38.9 and p < 0.0001; d = 16.0 versus control, respectively) (Fig.…”

Section: Resultssupporting

confidence: 87%

“…Although there are a variety of reports, including our own in pRCC [ 15 ], on the involvement of the related FFAR FFA4 on EMT in cancers, to our knowledge the current report is the first to demonstrate the role of FFA1 in this process. Consistent with our findings that FFA1 agonism inhibits cell migration and invasion, FFA1 agonism also decreased expression of the EMT markers vimentin and FN-1.…”

Section: Discussionmentioning

confidence: 64%

“…Immunoblotting was performed as we have previously described [ 15 – 17 ]. Representative blots are shown for experiments performed 3–5 times as described in the figure legends.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we reported the first evidence that FFAR may play functionally significant roles in RCC, as agonism of FFA4 was shown to stimulate pRCC migration and invasion, while at the same time inhibiting cell proliferation and tumor growth [ 15 ]. Here, we reveal for the first time that expression of FFA1 is increased in pRCC tissues from human tissue compared to patient-matched noncancerous adjacent kidney tissue, and that FFA1 expression is also associated with pathological progression of pRCC.…”

Section: Introductionmentioning

confidence: 99%

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Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT

Karmokar

Moniri

2023

Cancer Cell Int

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Background Papillary renal cell carcinoma (pRCC) is a highly metastatic genitourinary cancer and is generally irresponsive to common treatments used for the more prevalent clear-cell (ccRCC) subtype. The goal of this study was to examine the novel role of the free fatty-acid receptor-1 (FFA1/GPR40), a cell-surface expressed G protein-coupled receptor that is activated by medium-to-long chained dietary fats, in modulation of pRCC cell migration invasion, proliferation and tumor growth. Methods We assessed the expression of FFA1 in human pRCC and ccRCC tumor tissues compared to patient-matched non-cancerous controls, as well as in RCC cell lines. Using the selective FFA1 agonist AS2034178 and the selective FFA1 antagonist GW1100, we examined the role of FFA1 in modulating cell migration, invasion, proliferation and tumor growth and assessed the FFA1-associated intracellular signaling mechanisms via immunoblotting. Results We reveal for the first time that FFA1 is upregulated in pRCC tissue compared to patient-matched non-cancerous adjacent tissue and that its expression increases with pRCC cancer pathology, while the inverse is seen in ccRCC tissue. We also show that FFA1 is expressed in the pRCC cell line ACHN, but not in ccRCC cell lines, suggesting a unique role in pRCC pathology. Our results demonstrate that FFA1 agonism promotes tumor growth and cell proliferation via c-Src/PI3K/AKT/NF-κB and COX-2 signaling. At the same time, agonism of FFA1 strongly inhibits migration and invasion, which are mechanistically mediated via inhibition of EGFR, ERK1/2 and regulators of epithelial–mesenchymal transition. Conclusions Our data suggest that FFA1 plays oppositional growth and migratory roles in pRCC and identifies this receptor as a potential target for modulation of pathogenesis of this aggressive cancer.

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 64%

“…Immunoblotting was performed as we have previously described [ 15 – 17 ]. Representative blots are shown for experiments performed 3–5 times as described in the figure legends.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT

Karmokar

Moniri

2023

Cancer Cell Int

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“…The hepatocyte growth factor receptor (MET) kinase inhibitor Cabozantinib treatment could suppress the metastasis of PRCC and resulted in longer progression-free survival than sunitinib in patients with metastatic PRCC 43 . Functions of fatty acid in the regulation of migration and invasion have been studied in PRCC and could be an attractive target for studies of PRCC therapy 44 , 45 . EMT is a morphologic transformation process of epithelial cells to a mesenchymal phenotype, which promotes tumor cell migration, invasion, and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

Chu,

Xie,

Guo

et al. 2023

Annals of Medicine &Amp; Surgery

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Background: Our previous study has suggested that blocking stanniocalcin 2 (STC2) could reduce sunitinib resistance in clear cell renal cell carcinoma (ccRCC) under normoxia. The hypoxia is a particularly important environment for RCC occurrence and development, as well as sunitinib resistance. We proposed that STC2 also plays important roles in RCC sunitinib resistance under hypoxia conditions. Methods: The ccRCC Caki-1 cells were treated within the hypoxia conditions. Real-time quantitative PCR and Western blotting were applied to detect the STC2 expression in ccRCC Caki-1 cells. STC2-neutralizing antibodies, STC2 siRNA, and the recombinant human STC2 (rhSTC2) were used to identify targeting regulation on STC2 in modulating sunitinib resistance, proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. In addition, autophagy flux and the lysosomal acidic environment were investigated by Western blotting and fluorescence staining, and the accumulation of sunitinib in cells was observed with the addition of STC2-neutralizing antibodies and autophagy modulators. Results: Under hypoxia conditions, sunitinib disrupted the lysosomal acidic environment and accumulated in Caki-1 cells. Hypoxia induced the STC2 mRNA and protein levels in Caki-1 cells. STC2-neutralizing antibodies and STC2 siRNA effectively aggravated sunitinib-reduced cell viability and proliferation, which were reversed by rhSTC2. In addition, sunitinib promoted EMT, migration, and invasion, which were reduced by STC2-neutralizing antibodies. Conclusion: Inhibiting STC2 could reduce sunitinib resistance of ccRCC cells under hypoxia conditions.

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Metabolic Signaling in Cancer Metastasis

Krieg,

Fernandes,

Kolliopoulos

et al. 2024

Cancer Discovery

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Metastases, which are the leading cause of death in patients with cancer, have metabolic vulnerabilities. Alterations in metabolism fuel the energy and biosynthetic needs of metastases but are also needed to activate cell state switches in cells leading to invasion, migration, colonization, and outgrowth in distant organs. Specifically, metabolites can activate protein kinases as well as receptors and they are crucial substrates for posttranslational modifications on histone and nonhistone proteins. Moreover, metabolic enzymes can have moonlighting functions by acting catalytically, mainly as protein kinases, or noncatalytically through protein–protein interactions. Here, we summarize the current knowledge on metabolic signaling in cancer metastasis. Significance: Effective drugs for the prevention and treatment of metastases will have an immediate impact on patient survival. To overcome the current lack of such drugs, a better understanding of the molecular processes that are an Achilles heel in metastasizing cancer cells is needed. One emerging opportunity is the metabolic changes cancer cells need to undergo to successfully metastasize and grow in distant organs. Mechanistically, these metabolic changes not only fulfill energy and biomass demands, which are often in common between cancer and normal but fast proliferating cells, but also metabolic signaling which enables the cell state changes that are particularly important for the metastasizing cancer cells.

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Free-Fatty Acid Receptor-4 (FFA4/GPR120) differentially regulates migration, invasion, proliferation and tumor growth of papillary renal cell carcinoma cells

Cited by 4 publications

References 69 publications

Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT

Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT

Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

Metabolic Signaling in Cancer Metastasis

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