PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway

Her, Nam Gu; Jeong, Seong In; Cho, Kyucheol; Ha, Tae Kyu; Han, Jikhyon; Ko, Kwanyoung; Park, Soon Ki; Lee, Jin Hee; Lee, Min Goo; Ryu, Byeol; Gil, Sung

doi:10.4161/cc.24636

Cited by 32 publications

(24 citation statements)

References 41 publications

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“…Recent studies have shown that caveolin-1 affects signaling pathways involved in fibrogenesis, including internalization of the TGF-␤ receptor (Gvaramia et al 2013;Her et al 2013;Shi et al 2013). Here, we have shown that the STAT signaling pathway may represent a primary target for caveolin-1 regulation with respect to the antiproliferative properties of this protein.…”

Section: Discussionmentioning

confidence: 98%

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

Ryter

Choi

Kim

2014

Biochem. Cell Biol.

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Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1(-/-)) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1(-/-) fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1(-/-) liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis.

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Section: Discussionmentioning

confidence: 98%

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

Ryter

Choi

Kim

2014

Biochem. Cell Biol.

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“…At the time of this writing, only 2 other studies have linked PPARD to EMT: In one study, PPARD was reported to promote EMT by enhancing SRC signaling to drive ultraviolet light-driven skin tumorigenesis (22), and in another study, PPARD agonists were reported to upregulate SNAIL expression in melanoma cells, enhancing their migration and invasion in vitro (21). Previous studies have also shown that PPARD downregulation by siRNA in PC3 prostate cancer cells inhibited cell migration and matrix metalloproteinase-9 and caveolin 1 expression in vitro (66) and that pharmaceutical inhibition of PPARD suppressed MDA-MB-231 breast cancer cell invasion via the downregulation of TGF-β-angiopoietin-like 4 signaling (20). Although these previous studies' in vitro findings support PPARD's pro-metastatic role in cancer, the present study's findings provide mechanistic insights into how PPARD expression in cancer cells regulates cancer cell invasion, migration, and metastasis that are supported with in vivo metastasis modeling and whose translational relevance is established with data sets from large patient cohorts.…”

Section: Discussionmentioning

confidence: 99%

Metastasis regulation by PPARD expression in cancer cells

Zuo¹,

Xu²,

Xu³

et al. 2017

JCI Insight

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“…In addition, transforming growth factor (TGF)-β signaling plays a key role in prostate cancer occurrence and maintenance of cancer stem cell characteristics. The growth inhibitory effect of TGF-β may be due to overexpression of ABCA1 in prostate cancer cells (23). The expression of ABCA1 is associated with nuclear receptor of liver X receptor (LXR) and LXR forms a heterodimer with retinoid X receptor and regulates transcription of ABCA1 by binding to the DR-4 promoter element (24).…”

Section: Effect Of Abca1 On the Progression Of Prostate Cancermentioning

confidence: 99%

ATP‑binding cassette transporter A1: A promising therapy target for prostate cancer (Review)

Xiong

Huang

et al. 2017

mol clin onc

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Abstract. ATP-binding cassette transporter A1 (ABCA1) has been found to mediate the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I (apoA-I), and is essential for the synthesis of high-density lipoprotein.Mutations of the ABCA1 gene may induce Tangier disease and familial hypoalphalipoproteinemia; they may also lead to loss of cellular cholesterol homeostasis in prostate cancer, and increased intracellular cholesterol levels are frequently found in prostate cancer cells. Recent studies have demonstrated that ABCA1 may exert anticancer effects through cellular cholesterol efflux, which has been attracting increasing attention in association with prostate cancer. The aim of the present review was to focus on the current views on prostate cancer progression and the various functions of ABCA1, in order to provide new therapeutic targets for prostate cancer.

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PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway

Cited by 32 publications

References 41 publications

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

Metastasis regulation by PPARD expression in cancer cells

ATP‑binding cassette transporter A1: A promising therapy target for prostate cancer (Review)

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