Diverse effects of G-protein-coupled free fatty acid receptors on the regulation of cellular functions in lung cancer cells

Kita, Tsubasa; Kadochi, Yui; Takahashi, Kazuhisa; Fukushima, Kaori; Yamasaki, Eri; Uemoto, Taiki; Hirane, Miku; Fukushima, Nobuyuki; Honoki, Kanya; Tsujiuchi, Toshifumi

doi:10.1016/j.yexcr.2016.03.008

Cited by 27 publications

(20 citation statements)

References 25 publications

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“…In islet β cells, GPR40 activation increases insulin resistance, whereas GPR120 activation increases insulin sensitivity (29). The motility and invasion of melanoma, lung and pancreatic cancer cell lines are enhanced by GPR40, but suppressed by GPR120 (30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Pro-metastatic intracellular signaling of the elaidic trans fatty acid

Fujii

Luo

Fujiwara‐Tani

et al. 2016

International Journal of Oncology

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Trans fatty acids (TFAs) are risk factors of cardiovascular disorders, and a few studies have reported the cancer-promoting effects of TFAs. In the present study, we examined the effects and signaling of elaidic acid (EA), a TFA, in colorectal cancer (CRC) cells. Oral intake of EA increased the metastasis of CT26 mouse CRC cells by inducing the expression of stemness markers nucleostemin (NS) and CD133. Mechanisms underlying EA-induced signaling were confirmed by determining the binding of EA to G-protein coupled receptor 40 (GPR40) and GPR120 by performing surface protein internalization assay. We found that c-SRC mediated EGFR transactivation was induced by the binding of EA to GPR40 and GPR120. Moreover, EGFR signaling upregulated NS and Snail expression and downregulated E-cadherin expression in wild-type APC-containing CT26 cells, and upregulated NS, Wnt5a and CD44 expression in APC-null HT29 cells. These results indicate that EA enhances the stemness and epithelial-mesenchymal transition of CRC cells. These results also indicate the prominent metastatic potential of EA-treated cancer cells and highlight the important implications of EA on public health.

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Section: Discussionmentioning

confidence: 99%

Pro-metastatic intracellular signaling of the elaidic trans fatty acid

Fujii

Luo

Fujiwara‐Tani

et al. 2016

International Journal of Oncology

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“…18,20 However, in contrast to these pro-tumorigenic effects, Nehra, Pan 19 demonstrated decreased melanoma cell proliferation in vitro and decreased tumour growth in a murine tumour model in response to DHA or the synthetic GPR40 agonist TAK-875. 18,20 However, in contrast to these pro-tumorigenic effects, Nehra, Pan 19 demonstrated decreased melanoma cell proliferation in vitro and decreased tumour growth in a murine tumour model in response to DHA or the synthetic GPR40 agonist TAK-875.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding possible functional aspects, Fukushima, Takahashi 20 and Kita, Kadochi 18 were able to show that activation of GPR40 with the synthetic GPR40 agonist GW9508 enhanced cell motility in melanoma and lung cancer cells, whereas selective GPR40 inhibition reduced cell motility in melanoma cells. 18,20 However, in contrast to these pro-tumorigenic effects, Nehra, Pan 19 demonstrated decreased melanoma cell proliferation in vitro and decreased tumour growth in a murine tumour model in response to DHA or the synthetic GPR40 agonist TAK-875. In breast cancer cells both, tumour-promoting and tumourinhibiting effects were described with different GPR40 receptor agonists.…”

Section: Discussionmentioning

confidence: 99%

“…9 Interestingly, GPR40 is also expressed in several cancer cells. [15][16][17][18] Regarding the role of GPR40 in malignant melanoma, only limited data are available. 10,11 Soto-Guzman, Robledo 12 postulated a GPR40-dependent signal transduction pathway in breast cancer cells leading to ERK1/2 activity and transactivation of the epidermal growth factor receptor (EGFR) promoting cancer cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…In summary, GPR40 activation inhibited cell motility and cell invasion in pancreas carcinoma, osteosarcoma and fibrosarcoma cells, whereas in lung carcinoma GPR40 activation stimulated cell motility and cell invasion. [15][16][17][18] Regarding the role of GPR40 in malignant melanoma, only limited data are available. Recently, Nehra, Pan 19 demonstrated elevated levels of GPR40 expression in melanoma cell lines.…”

Section: Introductionmentioning

confidence: 99%

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G protein‐coupled receptor 40 expression in human melanoma – correlation with tumour thickness, AJCC stage and survival

Kleemann

Hrgović

Kleimann

et al. 2019

Acad Dermatol Venereol

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Background In melanoma, preclinical data suggest a possible role of polyunsaturated fatty acids inhibiting cell growth. A new target molecule for free fatty acids, the G protein‐coupled receptor GPR40, was identified in melanoma cells. Objectives The aim of this study was to investigate GPR40 expression in human melanocytic tissues and to evaluate its potential as a prognostic marker. Methods and Results A total of 114 tissue sections of naevi, primary melanoma and melanoma metastasis were immunohistochemically stained with anti‐GPR40. The staining was evaluated, using the immunoreactivity scoring system. Compared to naevi, primary melanoma and melanoma metastasis showed significantly higher levels of GPR40 (P < 0.05). In primary melanoma, GPR40 expression positively correlated with tumour thickness (P = 0.044) and AJCC level (P = 0.017) and in melanoma metastasis with AJCC level (P = 0.035). Primary melanoma patients with high levels of GPR40 had a significantly poorer overall survival (P = 0.004) and shorter disease‐free survival (0.040). Conclusion The present study identified GPR40 as a novel target molecule in melanoma. First evidence for a potential role of the receptor in tumour progression and metastases was found, and it could be demonstrated that GPR40 expression is negatively correlated with patient's survival.

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Oleic acid promotes prostate cancer malignant phenotype via the G protein‐coupled receptor FFA1/GPR40

Liotti¹,

Cosimato²,

Mirra³

et al. 2018

Journal Cellular Physiology

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Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related death in industrialized countries. Epidemiologic evidence suggests that obesity promotes aggressive PCa. Recently, a family of Free Fatty Acid (FFA) receptors (FFARs) has been identified and reported to affect several crucial biological functions of tumor cells such as proliferation, invasiveness, and apoptosis. Here we report that oleic acid (OA), one of the most prevalent FFA in human plasma, increases proliferation of highly malignant PC3 and DU-145 PCa cells. Furthermore, docetaxel cytotoxic action, the first-line chemotherapeutic agent for the treatment of androgen-independent PCa, was significantly reduced in the presence of OA, when measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, suggesting that this FFA plays also a role in chemoresistance. OA induced intracellular calcium increase, in part due to the store operated calcium entry (SOCE), measured by a calcium imaging technique. Moreover, PI3K/Akt signaling pathway was enhanced, as revealed by increased Akt phosphorylation levels. Intriguingly, attenuating the expression of FFA1/GPR40, a receptor for long chain FFA including OA, prevented the OA-induced effects. Of relevance, we found that FFA1/GPR40 is significantly overexpressed in tissue specimens of PCa, compared to benign prostatic hyperplasia tissues, at both mRNA and protein expression level, analyzed by Real Time RT-PCR and immunofluorescence experiments, respectively. Our data suggest that OA promotes an aggressive phenotype in PCa cells via FFA1/GPR40, calcium and PI3K/Akt signaling. Thus, FFA1/GPR40, might represent a potential useful prognostic biomarker and therapeutic target for the treatment of advanced PCa.

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Diverse effects of G-protein-coupled free fatty acid receptors on the regulation of cellular functions in lung cancer cells

Cited by 27 publications

References 25 publications

Pro-metastatic intracellular signaling of the elaidic trans fatty acid

Pro-metastatic intracellular signaling of the elaidic trans fatty acid

G protein‐coupled receptor 40 expression in human melanoma – correlation with tumour thickness, AJCC stage and survival

Oleic acid promotes prostate cancer malignant phenotype via the G protein‐coupled receptor FFA1/GPR40

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