Overexpression of Fatty Acid Synthase in Middle Eastern Epithelial Ovarian Carcinoma Activates AKT and Its Inhibition Potentiates Cisplatin-Induced Apoptosis

Uddin, Shahab; Jehan, Zeenath; Ahmed, Maqbool; Alyan, Aisha; Al-Dayel, Fouad; Hussain, Azhar; Bavi, Prashant; Al-Kuraya, Khawla S

doi:10.2119/molmed.2011.00046

Cited by 28 publications

(34 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5C). Consistent with several studies showing the connection between upregulation of lipogenesis and activation of Akt (7, 8), we observed a decrease in phosphorylation of Akt in both KM20 and HT29 cell lines with stable knockdown of either ACLY or FASN (Fig. 5D).…”

Section: Resultssupporting

confidence: 92%

See 1 more Smart Citation

Inhibition of Fatty Acid Synthase Attenuates CD44-Associated Signaling and Reduces Metastasis in Colorectal Cancer

et al. 2012

View full text Add to dashboard Cite

Fatty Acid Synthase (FASN) and ATP-citrate lyase (ACLY), key enzymes of de novo lipogenesis, are significantly upregulated and activated in many cancers and portend poor prognosis. Even though the role of lipogenesis in providing proliferative and survival advantages to cancer cells has been described, the impact of aberrant activation of lipogenic enzymes on cancer progression remains unknown. In this study, we found that elevated expression of FASN is associated with advanced stages of colorectal cancer (CRC) and liver metastasis, suggesting that it may play a role in progression of CRC to metastatic disease. Targeted inhibition of lipogenic enzymes abolished expression of CD44, a transmembrane protein associated with metastases in several cancers including CRC. In addition, inhibition of lipogenic enzymes and reduced expression of CD44 attenuated the activation of MET, Akt, FAK, and paxillin, which are known to regulate adhesion, migration and invasion. These changes were consistent with an observed decrease in migration and adhesion of CRC cells in functional assays and with re-organization of actin cytoskeleton upon FASN inhibition. Despite the modest effect of FASN inhibition on tumor growth in xenografts, attenuation of lipogenesis completely abolished establishment of hepatic metastasis and formation of secondary metastasis. Together, our findings suggest that targeting de novo lipogenesis may be a potential treatment strategy for advanced CRC.

show abstract

Section: Resultssupporting

confidence: 92%

“…Neoplastic lipogenesis provides a selective proliferative and survival advantage and contributes to drug resistance in cancer cells (6–8). However, the impact of aberrant activation of lipogenic enzymes on metastases remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Fatty Acid Synthase Attenuates CD44-Associated Signaling and Reduces Metastasis in Colorectal Cancer

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Inhibiting key metabolic enzymes in the fatty acid synthesis pathway led to significant cell death in cisplatin‐resistant lung cancer cells . In addition, combination treatment of C75 and cisplatin resulted in growth inhibition of epithelial ovarian carcinoma xenografts in nude mice . Sequential cerulenin/cisplatin treatment reduced cisplatin's half maximal inhibitory concentration in cisplatin‐resistant ovarian cancer cells, suggesting platinum (re)sensitisation .…”

Section: Discussionmentioning

confidence: 99%

The effect of FASN inhibition on the growth and metabolism of a cisplatin‐resistant ovarian carcinoma model

Papaevangelou

Almeida

Box

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Overexpression of fatty acid synthase (FASN), a key regulator of the de novo synthesis of fatty acids, has been demonstrated in a variety of cancers and is associated with poor prognosis and increased multidrug resistance. Inhibition of FASN with the anti‐obesity drug orlistat has been shown to have significant anti‐tumourigenic effects in many cancers, notably breast and prostate. In our study, we investigated whether FASN inhibition using orlistat is an effective adjunctive treatment for ovarian cancers that have become platinum resistant using a cisplatin‐resistant ovarian tumour xenograft model in mice. Mice were treated with orlistat or cisplatin or a combination and metabolite analysis and histopathology were performed on the tumours ex vivo. Orlistat decreased tumour fatty acid metabolism by inhibiting FASN, cisplatin reduced fatty acid β‐oxidation, and combination treatment delayed tumour growth and induced apoptotic and necrotic cell death in cisplatin‐resistant ovarian cancer cells over and above that with either treatment alone. Combination treatment also decreased glutamine metabolism, nucleotide and glutathione biosynthesis and fatty acid β‐oxidation. Our data suggest that orlistat chemosensitised platinum‐resistant ovarian cancer to treatment with platinum and resulted in enhanced efficacy.

show abstract

“…Treatment with FAS small interfering RNA (siRNA) causes accumulation of malonyl‐CoA, which leads to inhibition of carnitine palmitoyltransferase I and up‐regulation of ceramide and induction of the proapoptotic genes BNIP3, tumor necrosis factor‐related apoptosis‐inducing ligand, and death‐associated protein kinase 2, resulting in apoptosis in breast tumor cells (Bandyopadhyay et al, 2006). In addition, FAS blockade by C75 (FAS inhibitor) or FAS siRNA inhibited proliferation and induced apoptosis in human ovarian carcinoma cell line and suppressed tumor growth in vivo (Uddin et al, 2011). FAS is therefore considered an ideal target for anticancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Mollugin inhibits proliferation and induces apoptosis by suppressing fatty acid synthase in HER2‐overexpressing cancer cells

Truong

Hwang

Kim

et al. 2013

Journal Cellular Physiology

View full text Add to dashboard Cite

Mollugin is a naphthohydroquine found in the roots of Rubia cordifolia, and has been reported to have a variety of biological activities, including anti-inflammatory and apoptotic effects. In the present study, we investigated the molecular mechanisms by which mollugin exerts anti-tumor effect in HER2-overexpressing cancer cells. Our results showed that mollugin exhibited potent inhibitory effects on cancer cell proliferation, especially in HER2-overexpressing SK-BR-3 human breast cancer cells and SK-OV-3 human ovarian cancer cells in a dose- and time-dependent manner without affecting immortalized normal mammary epithelial cell line MCF-10A. Furthermore, we found that a blockade of Akt/SREBP-1c signaling through mollugin treatment significantly reduced FAS expression and subsequently suppressed cell proliferation and induced apoptosis in HER2-overexpressing cancer cells. Mollugin treatment caused a dose-dependent inhibition of HER2 gene expression at the transcriptional level, potentially in part through suppression of NF-κB activation. The combination of mollugin with a MEK1/2 inhibitor may be required in order to achieve optimal efficacy in HER2-overexpressing cancers. These data provide evidence that mollugin inhibits proliferation and induces apoptosis in HER2-overexpressing cancer cells by blocking expression of the FAS gene through modulation of a HER2/Akt/SREBP-1c signaling pathway. Our findings suggest that mollugin is a novel modulator of the HER2 pathway in HER2-overexpressing cancer cells with a potential role in the treatment and prevention of human breast and ovarian cancer with HER2 overexpression.

show abstract

Overexpression of Fatty Acid Synthase in Middle Eastern Epithelial Ovarian Carcinoma Activates AKT and Its Inhibition Potentiates Cisplatin-Induced Apoptosis

Cited by 28 publications

References 30 publications

Inhibition of Fatty Acid Synthase Attenuates CD44-Associated Signaling and Reduces Metastasis in Colorectal Cancer

Inhibition of Fatty Acid Synthase Attenuates CD44-Associated Signaling and Reduces Metastasis in Colorectal Cancer

The effect of FASN inhibition on the growth and metabolism of a cisplatin‐resistant ovarian carcinoma model

Mollugin inhibits proliferation and induces apoptosis by suppressing fatty acid synthase in HER2‐overexpressing cancer cells

Contact Info

Product

Resources

About