Biochemical changes accompanying apoptotic cell death in retinoblastoma cancer cells treated with lipogenic enzyme inhibitors

Vandhana, Suryanarayanan; Coral, Karunakaran; Jayanthi, U; Deepa, Perinkulam Ravi; Krishnakumar, Subramanian

doi:10.1016/j.bbalip.2013.06.005

Cited by 29 publications

(30 citation statements)

References 35 publications

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“…FASN activity in cellular extracts of HepG2 cells was determined by detection of long chain free fatty acid, the product of the de novo fatty acid synthesis pathway, using the Free Fatty Acid Quantification Kit (Abcam) and (BioVision, CA, USA) [22], [37] as described in the manufacturer’s protocol. The principle of this assay was based on the conversion of long chain free fatty acids to CoA derivatives, which were subsequently oxidized.…”

Section: Methodsmentioning

confidence: 99%

“…The concentration of triglycerides in the cells was determined by the Triglyceride Quantification Kit (Abcam) [22]. HepG2 cells were seeded at a density of 1×10 6 cells/60 mm 3 petri dish and allowed an overnight period of attachment.…”

Section: Methodsmentioning

confidence: 99%

“…It has been reported that supplementing cells with palmitate, stearate, or oleate ameliorates the fatty acid depletion-induced cytotoxic effect in cancer cells, suggesting an important role of the de novo synthesis of fatty acid for cancer cell viability [21]. The pharmacological anti-cancer agents, including cerulenin, C75, triclosan, and orlistat, have been extensively evaluated in various cancer cells to exert apoptosis through anti-fatty acid synthesis activity [22]. Besides the use of pharmacological fatty acid synthesis inhibitors as anti-cancer drugs, the mechanism of capsaicin-induced apoptosis via targeting the de novo fatty acid synthesis inhibition will provide a new perspective benefit to suppress cancer.…”

Section: Introductionmentioning

confidence: 99%

“…This suggests that the de novo synthesis of LCFAs by inhibition of FASN in cancer cells becomes a focus for the selective target of anti-cancer therapeutics [30], [31], [32], [33]. The biological mechanisms of apoptosis induction by inhibition of FASN and fatty acid synthesis has been reported to be due to the lack of the end product LCFA per se , or the downstream toxic effects of an increase of the malonyl-CoA synthesis pathway [22].…”

Section: Introductionmentioning

confidence: 99%

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The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

et al. 2014

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The inhibition of the mammalian de novo synthesis of long-chain saturated fatty acids (LCFAs) by blocking the fatty acid synthase (FASN) enzyme activity in tumor cells that overexpress FASN can promote apoptosis, without apparent cytotoxic to non-tumor cells. The present study aimed to focus on the potent inhibitory effect of capsaicin on the fatty acid synthesis pathway inducing apoptosis of capsaicin in HepG2 cells. The use of capsaicin as a source for a new FASN inhibitor will provide new insight into its possible application as a selective anti-cancer therapy. The present findings showed that capsaicin promoted apoptosis as well as cell cycle arrest in the G0/G1 phase. The onset of apoptosis was correlated with a dissipation of mitochondrial membrane potential (ΔΨm). Apoptotic induction by capsaicin was mediated by inhibition of FASN protein expression which was accompanied by decreasing its activity on the de novo fatty acid synthesis. The expression of FASN was higher in HepG2 cells than in normal hepatocytes that were resistant to undergoing apoptosis following capsaicin administration. Moreover, the inhibitory effect of capsaicin on FASN expression and activity was found to be mediated by an increase of intracellular reactive oxygen species (ROS) generation. Treatment of HepG2 cells with capsaicin failed to alter ACC and ACLY protein expression, suggesting ACC and ACLY might not be the specific targets of capsaicin to induce apoptosis. An accumulation of malonyl-CoA level following FASN inhibition represented a major cause of mitochondrial-dependent apoptotic induction instead of deprivation of fatty acid per se. Here, we also obtained similar results with C75 that exhibited apoptosis induction by reducing the levels of fatty acid without any change in the abundance of FASN expression along with increasing ROS production. Collectively, our results provide novel evidence that capsaicin exhibits a potent anti-cancer property by targeting FASN protein in HepG2 cells.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

et al. 2014

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“…Importantly, FASN support membrane phospholipid synthesis in prostate cancer cells, which may be implicated in signal transduction, intracellular trafficking, cell polarization, and migration (56). Finally, FASN inhibition increases polyunsaturation and decreases monounsaturation levels leading to lipid peroxidation, oxidative stress, and apoptosis (57,58).…”

Section: Discussionmentioning

confidence: 99%

The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas

Agostini

Almeida

Bastos

et al. 2014

Molecular Cancer Therapeutics

111

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Fatty acid synthase (FASN) is the biosynthetic enzyme responsible for the endogenous synthesis of fatty acids. It is downregulated in most normal cells, except in lipogenic tissues such as liver, lactating breast, fetal lung, and adipose tissue. Conversely, several human cancers, including head and neck squamous cell carcinomas (HNSCC), overexpress FASN, which has been associated with poor prognosis and recently suggested as a metabolic oncoprotein. Orlistat is an irreversible inhibitor of FASN activity with cytotoxic properties on several cancer cell lines that inhibits tumor progression and metastasis in prostate cancer xenografts and experimental melanomas, respectively. To explore whether the inhibition of FASN could impact oral tongue squamous cell carcinoma (OTSCC) metastatic spread, an orthotopic model was developed by the implantation of SCC-9 ZsGreen LN-1 cells into the tongue of BALB/c nude mice. These cells were isolated through in vivo selection, show a more invasive behavior in vitro than the parental cells, and generate orthotopic tumors that spontaneously metastasize to cervical lymph nodes in 10 to 15 days only. SCC-9 ZsGreen LN-1 cells also exhibit enhanced production of MMP-2, ERBB2, and CDH2. The treatment with orlistat reduced proliferation and migration, promoted apoptosis, and stimulated the secretion of VEGFA 165b by SCC-9 ZsGreen LN-1 cells. In vivo, the drug was able to decrease both the volume and proliferation indexes of the tongue orthotopic tumors and, importantly, reduced the number of metastatic cervical lymph nodes by 43%. These results suggest that FASN is a potential molecular target for the chemotherapy of patients with OTSCC. Mol Cancer Ther; 13(3); 585-95. Ó2013 AACR.

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Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

et al. 2018

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Suppression of the expression or activities of enzymes that are involved in the synthesis of de novo lipogenesis ( DNL ) in cancer cells triggers cell death via apoptosis. The plasma membrane citrate transporter ( PMCT ) is the initial step that translocates citrate from blood circulation into the cytoplasm for de novo long‐chain fatty acids synthesis. This study investigated the antitumor effect of the PMCT inhibitor ( PMCT i) in inducing apoptosis by inhibiting the DNL pathway in HepG2 cells. The present findings showed that PMCT i reduced cell viability and enhanced apoptosis through decreased intracellular citrate levels, which consequently caused inhibition of fatty acid and triacylglycerol productions. Thus, as a result of the reduction in fatty acid synthesis, the activity of carnitine palmitoyl transferase‐1 ( CPT ‐1) was suppressed. Decreased CPT ‐1 activity also facilitated the disruption of mitochondrial membrane potential (ΔΨm) leading to stimulation of apoptosis. Surprisingly, primary human hepatocytes were not affected by PMCT i. Increased caspase‐8 activity as a consequence of reduction in fatty acid synthesis was also found to cause disruption of ΔΨm. In addition, apoptosis induction by PMCT i was associated with an enhanced reactive oxygen species generation. Taken together, we suggest that inhibition of the DNL pathway following reduction in citrate levels is an important regulator of apoptosis in HepG2 cells via suppression of CPT ‐1 activity. Thus, targeting the DNL pathway mediating CPT ‐1 activity by PMCT i may be a selective potential anticancer therapy.

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Biochemical changes accompanying apoptotic cell death in retinoblastoma cancer cells treated with lipogenic enzyme inhibitors

Cited by 29 publications

References 35 publications

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas

Suppressed de novo lipogenesis by plasma membrane citrate transporter inhibitor promotes apoptosis in HepG2 cells

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