Trophoblastic Neoplasms Express Fatty Acid Synthase, Which May Be a Therapeutic Target via Its Inhibitor C93

Ueda, Stefanie; Mao, Tsui Lien; Kuhajda, Francis P.; Vasoontara, Chanont; Giuntoli, Robert L.; Bristow, Robert E.; Kurman, Robert J.; Shih, Ie Ming

doi:10.2353/ajpath.2009.081162

Cited by 17 publications

(13 citation statements)

References 32 publications

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“…FASN is involved in the synthesis of long chain saturated fatty acids, which are components of lipid rafts on the cell membrane that form sites of transmembrane protein localization. Treatment with a FASN inhibitor inhibited cell growth in vitro and in vivo , reduced PI3K signaling, and induced the apoptosis of chemoresistant ovarian cancer cells . Not only is FASN upregulated in our model of EOC development derived from ovarian surface epithelial cells, but FASN is also upregulated in early EOC precursor lesions in the fallopian tube, which are also cells of origin for a subset of ovarian cancers, further evidence to suggest that FASN may be a reliable biomarker of early‐stage EOC …”

Section: Discussionsupporting

confidence: 57%

“…FASN was also frequently expressed in EOC specimens. FASN has also not previously been reported as a diagnostic biomarker for EOC, but it is known to be overexpressed in many cancers and has been proposed as a therapeutic target in ovarian cancer and other malignancies . FASN expression is positively correlated with ER and PR expression in endometrial cancer and has been implicated in ERBB receptor signaling in ovarian cancer .…”

Section: Discussionmentioning

confidence: 99%

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Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three‐dimensional genetic models of ovarian carcinogenesis

Lawrenson

Mhawech‐Fauceglia

Worthington

et al. 2015

Intl Journal of Cancer

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Epithelial ovarian cancer (EOC) is still considered the most lethal gynecological malignancy and improved early detection of ovarian cancer is crucial to improving patient prognoses. To address this need, we tested whether candidate EOC biomarkers can be identified using three-dimensional (3D) in vitro models. We quantified changes in the abundance of secreted proteins in a 3D genetic model of early-stage EOC, generated by expressing CMYC and KRAS G12V in TERT-immortalized normal ovarian epithelial cells. Cellular proteins were labeled in live cells using stable isotopic amino acid analogues, and secreted proteins identified and quantified using liquid chromatography-tandem mass spectrometry. Thirty-seven and 55 proteins were differentially expressed by CMYC and CMYC1KRAS G12V expressing cells respectively (p < 0.05; >2-fold). We evaluated expression of the top candidate biomarkers in~210 primary EOCs: CHI3L1 and FKBP4 are both expressed by >96% of primary EOCs, and FASN and API5 are expressed by 86 and 75% of cases. High expression of CHI3L1 and FKBP4 was associated with worse patient survival (p 5 0.042 and p 5 0.002, respectively). Expression of LGALS3BP was positively associated with recurrence (p 5 0.0001) and suboptimal debulking (p 5 0.018) suggesting that these proteins may be novel prognostic biomarkers. Furthermore, within early stage tumours (I/II), high expression of API5, CHI3L1 and FASN was associated with high tumour grade (p 5 3 3 10 24 , p 5 0.016, p 5 0.010, respectively). We show in vitro cell biology models of early-stage cancer development can be used to identify novel candidate biomarkers for disease, and report the identification of proteins that represent novel potential candidate diagnostic and prognostic biomarkers for this highly lethal disease.Despite recent advances in surgery and chemotherapy, epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy, mainly due to the absence of specific symptoms and a lack of effective screening tools. The majority of patients present with advanced stage disease where the 5-year survival rate is only 27%. For advanced stage tumours, recurrence rates are over 60%, and 20% of these patients respond poorly to platinum-based chemotherapy. Therefore, detecting patients with early EOC continues to be an urgent clinical need and it remains a clinical priority to detect highgrade serous EOC early during disease development.Given the difficulties accessing the ovary for biopsy and the rapid rate at which the most aggressive EOC subtypes progress, the identification of clinical biomarkers detectable in the blood would represent a significant advance for the identification of patients with EOC. Currently the most widely used ovarian cancer biomarker is serum CA125, and this marker is particularly good at detecting disease recurrence. A second marker, HE4, was approved in 2009 for monitoring ovarian cancer progression, and can be elevated

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three‐dimensional genetic models of ovarian carcinogenesis

Lawrenson

Mhawech‐Fauceglia

Worthington

et al. 2015

Intl Journal of Cancer

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“…Inhibiting FASN activity in vitro by pharmacological means or its message levels by small interfering RNA (siRNA) has been shown to stop cancer cell growth and induce apoptosis. As a consequence, many research groups have tried to exploit FASN as a target for cancer by developing inhibitors including C75, C93, EGCG (epigallocatechin gallate), G28UCM, orlistat, GSK2194069, and GSK837149A (Hardwicke et al, 2014; Kuhajda et al, 2000; Landis-Piwowar et al, 2007; McFadden et al, 2005; Oliveras et al, 2010; Orita et al, 2007; Puig et al, 2009, 2011; Thupari et al, 2002; Tian, 2006; Turrado et al, 2012; Ueda et al, 2009; Vazquez et al, 2008; Wang and Tian, 2001; Zhou et al, 2007). Despite these efforts, however, the majority of FASN inhibitors have failed to even advance in translational studies largely due selectivity issues in vivo resulting in unexpected toxicities.…”

Section: Introductionmentioning

confidence: 99%

Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2 + Breast Cancer

Alwarawrah

Hughes

Loiselle

et al. 2016

Cell Chemical Biology

126

111

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Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2(+) breast cancer, particularly when combined with carboplatin.

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“…A recent study has identified fatty acid synthase as a potential therapeutic target for GTD via its inhibitor C93. 45 In view of the fact that kinase inhibitors for the PAK family are being developed, 13,14 our present findings may provide new insight into PAK1 as a potential therapeutic target in GTD.…”

Section: Discussionmentioning

confidence: 76%

p21-Activated Kinase-1 Promotes Aggressive Phenotype, Cell Proliferation, and Invasion in Gestational Trophoblastic Disease

Siu

Yeung

Zhang

et al. 2010

The American Journal of Pathology

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Gestational trophoblastic disease (GTD) includes hydatidiform mole (HM), which can develop persistent gestational trophoblastic neoplasia requiring chemotherapy; choriocarcinoma, which is a frankly malignant tumor; placental site trophoblastic tumor; and epithelioid trophoblastic tumor. p21-Activated kinases (PAKs) promote malignant tumor progression. Therefore, this study investigated PAK1, PAK2, and p-PAK2 Ser 20 in the pathogenesis of GTD. By real-time PCR, PAK1 mRNA was significantly higher in HMs, particularly metastatic HMs (P ‫؍‬ 0.046) and HMs that developed persistent disease (P ‫؍‬ 0.011), when compared with normal placentas. By immunohistochemistry, significantly increased cytoplasmic PAK1 immunoreactivity in cytotrophoblasts was also detected in HMs (P ‫؍‬ 0.042) and choriocarcinomas (P ‫؍‬ 0.003). In addition, HMs that developed persistent disease displayed higher PAK1 immunoreactivity than those that regressed (P ‫؍‬ 0.016), and elevated PAK1 immunoreactivity was observed in placental site trophoblastic tumors. Indeed, there was significant positive correlation between PAK1 expression and the proliferative indices Ki-67 (P ‫؍‬ 0.016) and MCM7 (P ‫؍‬ 0.026). Moreover, higher PAK1 mRNA and protein expression was confirmed in the choriocarcinoma cell-lines JEG-3 and JAR; however, PAK2 mRNA and p-PAK2 immunoreactivity showed a similar expression pattern in normal first trimester placentas and GTD. Knockdown of PAK1 in JEG-3 and JAR reduced cell proliferation, migration, and invasion ability, up-regulated p16, and down-regulated vascular endothelial growth factor and MT1-MMP expression. This is the first report revealing the involvement of PAK1 in the pathogenesis and clinical progress of

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Trophoblastic Neoplasms Express Fatty Acid Synthase, Which May Be a Therapeutic Target via Its Inhibitor C93

Cited by 17 publications

References 32 publications

Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three‐dimensional genetic models of ovarian carcinogenesis

Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three‐dimensional genetic models of ovarian carcinogenesis

Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2 + Breast Cancer

p21-Activated Kinase-1 Promotes Aggressive Phenotype, Cell Proliferation, and Invasion in Gestational Trophoblastic Disease

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