Tristetraprolin inhibits mitochondrial function through suppression of α-Synuclein expression in cancer cells

Vo, Mai-Tram; Choi, Seong Hee; Lee, Ji-Heon; Hong, Chung Hwan; Kim, Jong Soo; Lee, Unn Hwa; Chung, Hyung-Min; Lee, Byung Ju; Park, Jeong Woo; Cho, Wha Ja

doi:10.18632/oncotarget.16706

Cited by 7 publications

(6 citation statements)

References 87 publications

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“…17 TTP inhibits α-synuclein expression in SH-SY5Y cells, which suggests its involvement in the α-synuclein deposition in PD. 18 This study reports abnormal TTP accumulation in a PD model for the first time. Interestingly, TTP accumulation does not cause PD but provides compensatory neuroprotection.…”

Section: Introductionmentioning

confidence: 74%

Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease

et al. 2020

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Tristetraprolin (TTP), an RNA-binding protein encoded by the ZFP36 gene, is vital for neural differentiation; however, its involvement in neurodegenerative diseases such as Parkinson's disease (PD) remains unclear. To explore the role of TTP in PD, an in vitro 1-methyl-4-phenylpyridinium (MPP +) cell model and an in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of PD were used. Transfection of small interfering (si)-TTP RNA upregulated pro-oxidative NOX2 expression and ROS formation, downregulated anti-oxidative GSH and SOD activity；si-TTP upregulated pro-apoptotic cleaved-caspase-3 expression, and downregulated antiapoptotic Bcl-2 expression; while overexpression (OE)-TTP lentivirus caused opposite effects. Through database prediction, luciferase experiment, RNA immunoprecipitation (RIP), and mRNA stability analysis, we evaluated the potential binding sites of TTP to 3′-untranslated regions (3′-UTR) of NOX2 mRNA. TTP affected the NOX2 luciferase activity by binding to two sites in the NOX2 3′-UTR. RIP-qPCR confirmed TTP binding to both sites, with a higher affinity for site-2. In addition, TTP reduced the NOX2 mRNA stability. si-NOX2 and antioxidant N-acetyl cysteine (NAC) reversed si-TTP-induced cell apoptosis. In MPTP-treated mice, TTP expression increased and was co-located with dopaminergic neurons. TTP also inhibited NOX2 and decreased the oxidative stress in vivo. In conclusion, TTP protects against dopaminergic oxidative injury by promoting NOX2 mRNA 15048 | SUN et al.

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Section: Introductionmentioning

confidence: 74%

Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease

et al. 2020

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“…We previously reported that TTP overexpression decreases mitochondrial potential and ATP production in cancer cells (Vo et al , 2017). We investigated whether TTP expression affected the glycolytic capacity of cancer cells.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, TTP overexpression decreased intracellular ATP in cancer cells. We previously reported that TTP induces mitochondrial dysfunction through down-regulation of α-synuclein (Vo et al , 2017). Thus, we hypothesize that even though we did not determine the effect of TTP overexpression on α-synuclein level, TTP overexpression might inhibit mitochondrial oxidative phosphorylation through down-regulation of α-synuclein.…”

Section: Discussionmentioning

confidence: 99%

“…Glycolytic genes including Glut1 and LDHA are induced by HIF-1α (Semenza et al , 1994), whose expression and activity are modulated by mitochondrial dysfunction (Chandel et al , 1998; Mansfield et al , 2005). Considering that TTP can induce mitochondrial dysfunction (Vo et al , 2017), it is possible that TTP may indirectly regulate the expression of Glut1 and LDHA by inducing mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

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Tristetraprolin-mediated hexokinase 2 expression regulation contributes to glycolysis in cancer cells

Kim

Choi

et al. 2019

MBoC

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Hexokinase 2 (HK2) catalyzes the first step of glycolysis and is up-regulated in cancer cells. The mechanism has not been fully elucidated. Tristetraprolin (TTP) is an AU-rich element (ARE)-binding protein that inhibits the expression of ARE-containing genes by enhancing mRNA degradation. TTP expression is down-regulated in cancer cells. We demonstrated that TTP is critical for down-regulation of HK2 expression in cancer cells. HK2 mRNA contains an ARE within its 3′-UTR. TTP binds to HK2 3′-UTR and enhances degradation of HK2 mRNA. TTP overexpression decreased HK2 expression and suppressed the glycolytic capacity of cancer cells, measured as glucose uptake and production of glucose-6-phosphate, pyruvate, and lactate. TTP overexpression reduced both the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR) of cancer cells. Ectopic expression of HK2 in cancer cells attenuated the reduction in glycolytic capacity, ECAR, and OCR from TTP. Taken together, these findings suggest that TTP acts as a negative regulator of HK2 expression and glucose metabolism in cancer cells.

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“…An increasing number of studies have validated the importance of TTP expression in human cancer (51)(52)(53)(54). The loss of TTP gene expression has been reported in various cancer types (51,53), and reduced TTP gene expression has been demonstrated to lead to cancer development (32,33,55).…”

Section: Discussionmentioning

confidence: 99%

Tristetraprolin activation by resveratrol inhibits the proliferation and metastasis of colorectal cancer cells

et al. 2018

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Resveratrol (RSV) is a polyphenolic compound that naturally occurs in grapes, peanuts and berries. Considerable research has been conducted to determine the benefits of RSV against various human cancer types. Tristetraprolin (TTP) is an AU-rich element-binding protein that regulates mRNA stability and has decreased expression in human cancer. The present study investigated the biological effect of RSV on TTP gene regulation in colon cancer cells. RSV inhibited the proliferation and invasion/metastasis of HCT116 and SNU81 colon cancer cells. Furthermore, RSV induced a dose-dependent increase in TTP expression in HCT116 and SNU81 cells. The microarray experiment revealed that RSV significantly increased TTP expression by downregulating E2F transcription factor 1 (E2F1), a downstream target gene of TTP and regulated genes associated with inflammation, cell proliferation, cell death, angiogenesis and metastasis. Although TTP silencing inhibited TTP mRNA expression, the expression was subsequently restored by RSV. Small interfering RNA-induced TTP inhibition attenuated the effects of RSV on cell growth. In addition, RSV induced the mRNA-decaying activity of TTP and inhibited the relative luciferase activity of baculoviral IAP repeat containing 3 (cIAP2), large tumor suppressor kinase 2 (LATS2), E2F1, and lin‑28 homolog A (Lin28) in HCT116 and SNU81 cells. Therefore, RSV enhanced the inhibitory activity of TTP in HCT116 and SNU81 cells by negatively regulating cIAP2, E2F1, LATS2, and Lin28 expression. In conclusion, RSV suppressed the proliferation and invasion/metastasis of colon cancer cells by activating TTP.

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Tristetraprolin inhibits mitochondrial function through suppression of α-Synuclein expression in cancer cells

Cited by 7 publications

References 87 publications

Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease

Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease

Tristetraprolin-mediated hexokinase 2 expression regulation contributes to glycolysis in cancer cells

Tristetraprolin activation by resveratrol inhibits the proliferation and metastasis of colorectal cancer cells

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