Fatty Acid Synthase and AKT Pathway Signaling in a Subset of Papillary Thyroid Cancers

Uddin, Shahab; Siraj, Abdul K.; Al‐Rasheed, Maha; Ahmed, Maqbool; Bu, Rong; Myers, Jeffrey N.; Al-Nuaim, Abdulrahman; Al-Sobhi, Saif S.; Al‐Dayel, Fouad; Bavi, Prashant; Hussain, Azhar R.; Al‐Kuraya, Khawla S.

doi:10.1210/jc.2008-0503

Cited by 70 publications

(57 citation statements)

References 34 publications

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“…The results in this study presented show activation of the intrinsic pathway of apoptosis by the release of cytochrome c from B16-F10 melanoma cell mitochondria following FASN chemical inhibition or knockdown, which was associated with caspase-9 and -3 activation in agreement with previous findings. 27,28,41,55 As the cytochrome c release was not related to MPT in our experiments, malonyl-CoA accumulation, palmitoyltransferase-1 inhibition, and Bcl-2 may be involved in this process. It has been shown that colon and breast cancer cells are more resistant to FASN blockage and malonyl-CoA accumulation when p53 is intact.…”

Section: Discussionmentioning

confidence: 52%

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Zecchin

Rossato

Raposo

et al. 2011

Laboratory Investigation

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Fatty acid synthase (FASN) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long-chain fatty acid, palmitate. In contrast to most normal cells, FASN is overexpressed in a variety of human cancers, including cutaneous melanoma, in which its levels of expression are associated with tumor invasion and poor prognosis. We have previously shown that FASN inhibition with orlistat significantly reduces the number of spontaneous mediastinal lymph node metastases following the implantation of B16-F10 mouse melanoma cells in the peritoneal cavity of C57BL/6 mice. In this study, we investigate the biological mechanisms responsible for the FASN inhibition-induced apoptosis in B16-F10 cells. Both FASN inhibitors, cerulenin and orlistat, significantly reduced melanoma cell proliferation and activated the intrinsic pathway of apoptosis, as demonstrated by the cytochrome c release and caspase-9 and -3 activation. Further, apoptosis was preceded by an increase in both reactive oxygen species production and cytosolic calcium concentrations and independent of p53 activation and mitochondrial permeability transition. Taken together, these findings demonstrate the mitochondrial involvement in FASN inhibition-induced apoptosis in melanoma cells.

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Section: Discussionmentioning

confidence: 52%

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Zecchin

Rossato

Raposo

et al. 2011

Laboratory Investigation

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“…The body weight and tumor volume of each mouse also was monitored weekly. The tumor volume was measured as described previously (37). After 5 wks of treatment, mice were euthanized and individual tumors were weighed and then snap frozen in liquid nitrogen for storage.…”

Section: Animals and Xenograft Studymentioning

confidence: 99%

Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer

Hussain

Al-Romaizan

Ahmed

et al. 2015

Mol Med

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Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) are two key components of PI3K/Akt/mTOR signaling pathway. Dysregulation of these pathways have been found in many cancers, including epithelial ovarian cancer (EOC), however, the role of mTOR has not been fully elucidated in Middle Eastern EOC. Therefore, we investigated the activation of mTOR complexes (mTORC1 and mTORC2) in a cohort of 156 EOC from Saudi Arabia by immunohistochemistry in a tissue microarray format. mTORC1 and mTORC2 were found to be activated in 55 of 146 (37.7%) and 63 of 140 (45%) of EOC samples, respectively. mTORC1 was significantly associated with mTORC2 (p < 0.0001) activation and both mTOR complexes were significantly associated with p-AKT (p = 0.0205 and 0.0298) and p-P70S6 (p < 0.0001 and 0.0035), respectively. Interestingly, mTOR activation incurred a poor progression-free survival (PFS) (p = 0.0188) in EOC. Next, the in vitro effect of inactivation of mTOR complexes was evaluated using a second-generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in EOC cell lines. Finally, we studied the in vivo effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC.

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“…Ob-R expression was categorized by doing an H score as previously described (Uddin et al 2008c). Each TMA spot was assigned an intensity score from 0 to 3, and proportion of the tumor staining for that intensity was recorded as 5% increments from a range of 0 to 100 (P0, P1-3).…”

Section: Immunohistochemistry Assessmentmentioning

confidence: 99%

Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma

Uddin¹,

Bavi²,

Siraj³

et al. 2010

Endocrine-Related Cancer

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The putative role of leptin and its receptor (Ob-R) in the pathogenesis of various primary human malignancies has been reported; however, their role in papillary thyroid cancer (PTC) has not yet been evaluated. We investigated the role of Ob-R in a large tissue microarray cohort of PTC followed by in vitro studies using a panel of PTC cell lines. Ob-R overexpression was seen in 80% PTCs and was significantly associated with poor disease-free survival (PZ0.0235). PTCs that overexpressed Ob-R showed a aggressive phenotype characterized by older age, extrathyroid extension, larger tumor size, nodal metastasis, advanced stage, tall cell variant histological subtype, and a poor disease-free survival (PZ0.0005, PZ0.0006, PZ0.0398, PZ0.0004, PZ0.0111, PZ0.0003, and PZ0.0235 respectively). However, Ob-R expression was not an independent prognostic marker to predict disease-free survival in multivariate analysis. PTCs with overexpression of Ob-R showed a significant direct association with overexpression of XIAP (P!0.0001) and Bcl-XL (P!0.0001). In vitro analysis showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of phosphatidylinisitol 3 0 kinase (PI3K)/protein kinase B (AKT) signaling pathway. Inhibition of PI3K activity by its inhibitor LY294002 abrogated leptin-mediated PI3K/AKT signaling. Gene silencing of Ob-R in PTC cells resulted in downregulation of phospho-AKT, Bcl-XL, and XIAP expression suggesting that leptin-mediated pathogenesis of PTC occurs via involvement of these downstream targets. Altogether, these data show that leptin plays an important role in PTC pathogenesis through PI3K/AKT pathway via Ob-R and is a potential prognostic marker associated with an aggressive phenotype and poor diseasefree survival.

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Fatty Acid Synthase and AKT Pathway Signaling in a Subset of Papillary Thyroid Cancers

Abstract: Our results suggest that FASN and activated AKT pathway may be a potential target for therapeutic intervention for the treatment of PTC.

Cited by 70 publications

References 34 publications

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis

Dual Targeting of mTOR Activity with Torin2 Potentiates Anticancer Effects of Cisplatin in Epithelial Ovarian Cancer

Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma

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