scholarly journals Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase

2010 ◽  
Vol 17 (2) ◽  
pp. 539-551 ◽  
Author(s):  
L Zeng ◽  
K M Biernacka ◽  
J M P Holly ◽  
C Jarrett ◽  
A A Morrison ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acids ◽  
Cell Death ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Cell Types ◽  
Chemotherapeutic Agents ◽  
Malignant Cells ◽  
Obesity And Diabetes ◽  
Ceramide Production

The prognosis for women with breast cancer is adversely affected by the comorbidities of obesity and diabetes mellitus (DM), which are conditions associated with elevated levels of circulating fatty acids, hyperglycaemia and hyperinsulinaemia. We investigated the effects of exposure of non-malignant and malignant human breast epithelial cells to elevated levels of fatty acids and glucose on their growth, survival and response to chemotherapeutic agents. We found that palmitate induced cell death in the non-malignant cells but not in the malignant cells, which was abrogated through the inhibition of ceramide production and by oleate but not by IGF1. Fatty acid synthase (FAS) is responsible for the de novo synthesis of fatty acids from sugars, and is over-expressed in many epithelial cancers. Abundance of FAS was higher in malignant cells than in non-malignant cells, and was up-regulated by IGF1 in both cell types. IGF-induced growth of non-malignant cells was unaffected by suppression of FAS expression, whereas that of malignant cells was blocked as was their resistance to palmitate-induced cell death. Palmitate did not affect cell proliferation, whereas oleate promoted the growth of non-malignant cells but had the opposite effect, that is, inhibition of IGF1-induced growth of malignant cells. However, when the phosphatidylinositol 3-kinase pathway was inhibited, oleate enhanced IGF1-induced growth in both cell types. Hyperglycaemia conferred resistance on malignant cells, but not on non-malignant cells, to chemotherapy-induced cell death. This resistance was overcome by inhibiting FAS or ceramide production. Understanding the mechanisms involved in the associations between obesity, DM and breast cancer may lead to more effective treatment regimens and new therapeutic targets.

scholarly journals Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Barbara Schroeder ◽  
Travis Vander Steen ◽  
Ingrid Espinoza ◽  
Chandra M. Kurapaty Venkatapoorna ◽  
Zeng Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cells ◽  
Fatty Acid Synthase ◽  
Xenograft Model ◽  
Fine Tuning ◽  
Bh3 Mimetic

AbstractInhibitors of the lipogenic enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted cancer therapies. However, little is known about the molecular determinants of cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the BCL-2 family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins BIM, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of BIM or PUMA, suggesting that FASN activity controls cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for apoptosis. FASN inhibition results in a heightened mitochondrial apoptosis priming, shifting cells toward a primed-for-death state “addicted” to the anti-apoptotic protein BCL-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/BCL-2 inhibitor ABT-263 (navitoclax) and the BCL-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.

Inhibition of USP2 Induces Apoptosis through Down Regulation of Fatty Acid Synthase and Cyclin D1 in Triple Negative Breast Cancer

2020 ◽  
Vol 17 (5) ◽  
pp. 425-432
Author(s):  
Nida Syed ◽  
Amber Ilyas ◽  
Farha Idrees ◽  
Zarina ◽  
Zehra Hashim
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Fatty Acid ◽  
Early Detection ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cell Line ◽  
Fatty Acid Synthase ◽  
Triple Negative ◽  
Cancer Cell Line

Background: Breast cancer is the most occurring cancer in women with high incidence rates both in developed and developing countries. Among different types of breast cancers, Triple Negative Breast Cancer (TNBC) is the most aggressive type as it lacks receptors of Estrogen, Progesterone and Human Epidermal Growth Factor Receptor 2, common diagnostic biomarkers for the disease. Since early detection of TNBC can save thousands of lives, there is a dire need to discover and develop effective and affordable methods for early detection. Different Post Translational Modifications (PTMs) have been proposed as potential biomarker for various clinical conditions. Ubiquitination is a type of PTM involved in the stability and regulation of cellular proteins. Objective: It is hypothesized that reticence of ubiquitination may lead to cell death. Current study focuses on the inhibition of Ubiquitin Specific Protease (USP), USP2 using its inhibitor, ML364 in HTB- 132 triple negative breast cancer cell line to induce cell death. The aim of the current study was to evaluate anticancer property of ML364 that might be a promising novel therapeutic agent for TNBC. Furthermore, current investigations focus on USP2 and their focal stabilizing substrates i.e. Fatty acid Synthase (FAS) and Cyclin D1 could be potential prognostic markers for the disease. Methods: Quantitative PCR of CyclinD1, USP2, MDM2, and Fatty Acid Synthase (FAS) was performed to identify the deubiquitination effect of ML364 in breast cancer cells, which complemented our results with studies on normal and breast cancerous tissue samples. Results: Expression of USP2 and its substrates Cyclin D1and FAS was found to be down regulated in ML364 treated breast cancer cell line whereas higher expression was observed in breast cancer tissue, indicating therapeutic potential of USP2 inhibitor. Conclusion: Our findings suggest that USP2, Cyclin D1 and FAS could be used as prognostic marker and therapeutic target for TNBC.

Reverse Screening Bioinformatics Approach to Identify Potential Anti Breast Cancer Targets Using Thymoquinone from Neutraceuticals Black Cumin Oil

2019 ◽  
Vol 19 (5) ◽  
pp. 599-609 ◽  
Author(s):  
Sumathi Sundaravadivelu ◽  
Sonia K. Raj ◽  
Banupriya S. Kumar ◽  
Poornima Arumugamand ◽  
Padma P. Ragunathan
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Cell Death ◽  
In Silico ◽  
Chemotherapeutic Agents ◽  
Normal Cells ◽  
Black Cumin ◽  
In Silico Docking ◽  
Wide Range

Background: Functional foods, neutraceuticals and natural antioxidants have established their potential roles in the protection of human health and diseases. Thymoquinone (TQ), the main bioactive component of Nigella sativa seeds (black cumin seeds), a plant derived neutraceutical was used by ancient Egyptians because of their ability to cure a variety of health conditions and used as a dietary food supplement. Owing to its multi targeting nature, TQ interferes with a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Additionally, TQ can specifically sensitize tumor cells towards conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy) and simultaneously minimize therapy-associated toxic effects in normal cells besides being cost effective and safe. TQ was found to play a protective role when given along with chemotherapeutic agents to normal cells. Methods: In the present study, reverse in silico docking approach was used to search for potential molecular targets for cancer therapy. Various metastatic and apoptotic targets were docked with the target ligand. TQ was also tested for its anticancer activities for its ability to cause cell death, arrest cell cycle and ability to inhibit PARP gene expression. Results: In silico docking studies showed that TQ effectively docked metastatic targets MMPs and other apoptotic and cell proliferation targets EGFR. They were able to bring about cell death mediated by apoptosis, cell cycle arrest in the late apoptotic stage and induce DNA damage too. TQ effectively down regulated PARP gene expression which can lead to enhanced cancer cell death. Conclusion: Thymoquinone a neutraceutical can be employed as a new therapeutic agent to target triple negative breast cancer which is otherwise difficult to treat as there are no receptors on them. Can be employed along with standard chemotherapeutic drugs to treat breast cancer as a combinatorial therapy.

scholarly journals Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1132
Author(s):  
Javier A. Menendez ◽  
Adriana Papadimitropoulou ◽  
Travis Vander Steen ◽  
Elisabet Cuyàs ◽  
Bharvi P. Oza-Gajera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Promoter Activity ◽  
Fatty Acid Synthase ◽  
Endocrine Resistance ◽  
Gene Promoter ◽  
Her2 Positive ◽  
Her2 Breast Cancer

The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity—an in vitro metric of tumorigenicity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.

scholarly journals A non-canonical Δ9-desaturase synthesizing palmitoleic acid identified in the thraustochytrid Aurantiochytrium sp. T66

2021 ◽  
Author(s):  
E-Ming Rau ◽  
Inga Marie Aasen ◽  
Helga Ertesvåg
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Palmitoleic Acid ◽  
Unsaturated Fatty Acids ◽  
Gene Annotation ◽  
Vaccenic Acid ◽  
Strain Engineering ◽  
Δ9 Desaturase ◽  
Δ12 Desaturase

Abstract Thraustochytrids are oleaginous marine eukaryotic microbes currently used to produce the essential omega-3 fatty acid docosahexaenoic acid (DHA, C22:6 n-3). To improve the production of this essential fatty acid by strain engineering, it is important to deeply understand how thraustochytrids synthesize fatty acids. While DHA is synthesized by a dedicated enzyme complex, other fatty acids are probably synthesized by the fatty acid synthase, followed by desaturases and elongases. Which unsaturated fatty acids are produced differs between different thraustochytrid genera and species; for example, Aurantiochytrium sp. T66, but not Aurantiochytrium limacinum SR21, synthesizes palmitoleic acid (C16:1 n-7) and vaccenic acid (C18:1 n-7). How strain T66 can produce these fatty acids has not been known, because BLAST analyses suggest that strain T66 does not encode any Δ9-desaturase-like enzyme. However, it does encode one Δ12-desaturase-like enzyme. In this study, the latter enzyme was expressed in A. limacinum SR21, and both C16:1 n-7 and C18:1 n-7 could be detected in the transgenic cells. Our results show that this desaturase, annotated T66Des9, is a Δ9-desaturase accepting C16:0 as a substrate. Phylogenetic studies indicate that the corresponding gene probably has evolved from a Δ12-desaturase-encoding gene. This possibility has not been reported earlier and is important to consider when one tries to deduce the potential a given organism has for producing unsaturated fatty acids based on its genome sequence alone. Key points • In thraustochytrids, automatic gene annotation does not always explain the fatty acids produced. • T66Des9 is shown to synthesize palmitoleic acid (C16:1 n-7). • T66des9 has probably evolved from Δ12-desaturase-encoding genes.

Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c

2003 ◽  
Vol 282 (2) ◽  
pp. 132-137 ◽  
Author(s):  
Y.u-A.n Yang ◽  
Patrice J. Morin ◽  
Wan Fang Han ◽  
Tinghua Chen ◽  
Daniel M. Bornman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Binding Protein ◽  
Regulatory Element ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Abstract PS17-26: Fatty acid synthase inhibition targets ERα in tamoxifen-resistant breast cancer

2021 ◽  
Author(s):  
Bryan Mcclellan ◽  
Aleksandra Gruslova ◽  
Christopher Jolly ◽  
Linda deGraffenried ◽  
Andrew Brenner
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Tamoxifen Resistant

Expression of BCL2L12, a new member of apoptosis-related genes, in breast tumors

2003 ◽  
Vol 89 (06) ◽  
pp. 1081-1088 ◽  
Author(s):  
Maroulio Talieri ◽  
Eleftherios Diamandis ◽  
Nikos Katsaros ◽  
Dimitrios Gourgiotis ◽  
Andreas Scorilas
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cox Regression ◽  
Breast Tumors ◽  
Cell Types ◽  
Research Society ◽  
Genetic Alterations ◽  
Cox Regression Analysis ◽  
Reverse Transcription Pcr ◽  
Lower Stage

SummaryApoptosis, a normal physiological form of cell death, is critically involved in the regulation of cellular homeostasis. If the delicate balance between cell death and cell proliferation is altered by a defect in the normal regulation of apoptosis signaling, a cell population is able to survive and accumulate, thereby favoring the acquisition of further genetic alterations and promoting tumorigenesis. Dysregulation of programmed cell death mechanisms plays an important role in the pathogenesis and progression of breast cancer, as well as in the responses of tumors to therapeutic intervention. Overexpression of anti-apoptotic members of the Bcl-2 family such as Bcl-2 and Bcl-XL has been implicated in cancer chemoresistance, whereas high levels of pro-apoptotic proteins such as Bax promote apoptosis and sensitize tumor cells to various anticancer therapies. Recently, a new member of the Bcl-2 family, BCL2L12, was cloned. The BCL2L12 gene is constitutively expressed in many tissues, suggesting that the encoded protein serves an important function in different cell types. In the present study, the expression of BCL2L12 gene was analyzed by reverse transcription-PCR (PT-PCR) in 70 breast cancer tissues. Our results indicate that BCL2L12 positive breast tumors are mainly of lower stage (I/II) or grade (I/II) (p=0.02 or p=0.04 respectively). Cox regression analysis revealed that BCL2L12 expression is positively related to disease-free (DFS) and overall survival (OS) at both univariate and multivariate analysis (p=0.021, p=0.029, p=0.032, p=0.044 respectively). Kaplan-Meier survival curves also demonstrated that patients with BCL2L12-positive tumors have significantly longer DFS and OS (p=0.002 and p<0.001 respectively). BCL2L12 expression may be regarded as a new independent favorable prognostic marker for breast cancer.Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

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