Downregulation of fatty acid synthase complex suppresses cell migration by targeting phospho-AKT in bladder cancer

Zheng, Shuaishuai; Gao, Jiangang; Liu, Zhijun; Zhang, Xinhong; Wu, Shuai; Weng, Bo-wen; Wang, You Lin; Hou, Shaozhen; Jiang, Bo

doi:10.3892/mmr.2015.4746

Cited by 21 publications

(13 citation statements)

References 44 publications

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“…In this survey, we found that FASN and SREBP-1c were undetectable in normal urothelial tissues but highly expressed in urothelial carcinoma tissues by immunohistochemistry ( Figure 1a) and western blot ( Figure 1b). As shown in Figure 1c, Zheng et al, 2015). We knocked down FASN (Figure 2a) and found that downregulation of FASN inhibited the cell proliferation on bladder cancer cells detected by MTT ( Figure 2b) and colony formation (Figure 2c).…”

Section: Fasn Is Highly Expressed In Bladder Tumor Tissue and Tumormentioning

confidence: 75%

“…FASN overexpression seems to play a crucial role in bladder cancer development (being associated with tumor cell survival and migration, high histological grade, tumor recurrence, and resistance to chemotherapy) (Chen, Chong, Yin, Luo, & Deng, ; Zheng et al, ). We knocked down FASN (Figure a ) and found that downregulation of FASN inhibited the cell proliferation on bladder cancer cells detected by MTT (Figure b) and colony formation (Figure c).…”

Section: Resultsmentioning

confidence: 99%

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Down‐regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP‐1c axis

Tao

et al. 2018

Journal Cellular Physiology

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Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c). We first discovered that PKM2 physically interacts with the SREBP-1c using biochemical approaches, and downregulation of PKM2 reduced the expression of SREBP-1c by inactivating the AKT/mTOR signaling pathway, which in turn directly suppressed the transcription of major lipogenic genes FASN to reduce tumor growths. Furthermore, either PKM2 inhibitor-Shikonin or FASN inhibitor-TVB-3166 alone induced a strong antiproliferative and anticolony forming effect in bladder cancer cell line. The combination of both inhibitors exhibits a super synergistic effect on blocking the bladder cancer cells growth. It provides a new target and scientific basis for the treatment of bladder cancer.

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Section: Fasn Is Highly Expressed In Bladder Tumor Tissue and Tumormentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Down‐regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP‐1c axis

Tao

et al. 2018

Journal Cellular Physiology

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“…These data suggested that FASN modulates the proliferation and metastasis of GC potentially via regulation of the mTOR/Gli1 signaling pathway. and FASN inhibition can also inactivate the activity of AKT in various types of cancer (29)(30)(31). Since the activation of AMPK and AKT serves a vital role in regulating mTOR activity in cancer (32), the present study assessed whether AMPK and AKT are involved in the regulation of FASN-mediated mTOR/Gli1 activation in GC.…”

Section: Resultsmentioning

confidence: 99%

“…In cancer cells, FASN is commonly overexpressed, providing cancer cells with an extra source of cellular fatty acids, and is significantly associated with tumor cell proliferation, metastasis and a poor prognosis (12)(13)(14)(15). Inhibition of tumor FASN activity attenuates tumor cell proliferation and metastasis, and induces apoptosis in vitro and in vivo (11,14,27,28,30,31), suggesting that FASN is an attractive target for cancer therapy. However, studies focusing upon FASN in GC are limited.…”

Section: Discussionmentioning

confidence: 99%

Small interfering RNA‑mediated knockdown of fatty acid synthase attenuates the proliferation and metastasis of human gastric cancer cells via the mTOR/Gli1 signaling pathway

et al. 2018

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Fatty acid synthase (FASN), the main enzyme involved in lipogenesis, is overexpressed in several types of tumor tissues. In addition, it is associated with tumor cell proliferation, metastasis, epithelial-mesenchymal transition (EMT) and a poor prognosis. However, the precise functions and internal mechanisms of FASN with regard to the proliferation, metastasis and EMT in gastric cancer (GC) cells remain elusive. The present study investigated FASN protein expression in 18 randomly selected pairs of GC tumors and matched normal tissues by western blot analysis. FASN-specific small interfering RNA (siRNA) was then transfected into SGC-7901 cells to examine the effect of FASN on proliferation and migration. Western blotting was used to detect the protein expression of FASN, EMT-related markers and key signaling molecules of the mechanistic target of rapamycin/zinc finger protein GLI1 (mTOR/Gli1) pathway. Reverse transcription-quantitative polymerase chain reaction was conducted to detect the mRNA expression of FASN and EMT-related markers. The FASN level was higher in the GC tissues compared with that in the surrounding normal tissues. Knockdown of FASN suppressed GC cell proliferation and metastasis . The silencing of FASN expression using siRNA reversed EMT at the protein and mRNA levels and decreased the expression of Gli1 via regulation of AMP-activated protein kinase/mTOR and protein kinase B/mTOR signaling in GC cells. Inhibition of FASN suppresses GC proliferation and metastasis through targeting of the mTOR/Gli1 signaling pathway, indicating that it may serve as a potential target for the treatment of GC.

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“…The Akt/mTOR signalling pathway also promotes the transcription of FASN, thereby forming a positive feedback regulation (45,46). The downregulation of FASN inhibited cancer cell invasion and migration by targeting the Akt/mTOR signalling pathway (47)(48)(49). A recent study reported that inactivation of FASN suppressed Akt-driven hepatocarcinogenesis in mice and humans (50).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-1207-5p inhibits hepatocellular carcinoma cell growth and invasion through the fatty acid synthase-mediated Akt/mTOR signalling pathway

et al. 2016

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Fatty acid synthase (FASN) has emerged as a unique oncologic target for the treatment of cancers, including hepatocellular carcinoma (HCC). However, effective inhibitors of FASN for cancer treatment are lacking. MicroRNAs (miRNAs) have emerged as novel and endogenic inhibitors of gene expression. In the present study, we aimed to investigate the role of miR‑1207‑5p in HCC and the regulation of FASN through miR‑1207‑5p. The expression of miR-1207-5p was markedly reduced in HCC tissues and cell lines as detected with real‑time quantitative polymerase chain reaction (qPCR). Overexpression of miR-1207-5p significantly suppressed the cell growth and invasion of HCC cells. By contrast, inhibition of miR‑1207‑5p exhibited an opposite effect. Bioinformatics analysis showed that FASN is a predicted target of miR‑1207‑5p which was validated by dual‑luciferase reporter assay, qPCR and western blot analysis. Overexpression of miR‑1207‑5p inhibited the Akt/mTOR signalling pathway, and promotion of this pathway was noted following inhibition of miR‑1207‑5p. Rescue experiments showed that the restoration of FASN expression partially reversed the inhibitory effect of miR‑1207‑5p on cell growth, invasion and Akt phosphorylation. In conclusion, our study suggests that miR‑1207‑5p/FASN plays an important role in HCC, and provides novel insight into developing new inhibitors for FASN for therapeutic interventions for HCC.

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Downregulation of fatty acid synthase complex suppresses cell migration by targeting phospho-AKT in bladder cancer

Cited by 21 publications

References 44 publications

Down‐regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP‐1c axis

Down‐regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP‐1c axis

Small interfering RNA‑mediated knockdown of fatty acid synthase attenuates the proliferation and metastasis of human gastric cancer cells via the mTOR/Gli1 signaling pathway

MicroRNA-1207-5p inhibits hepatocellular carcinoma cell growth and invasion through the fatty acid synthase-mediated Akt/mTOR signalling pathway

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