Fatty acid synthase inhibition: Metabolic reprogramming leading to cancer cell death

Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death

Oncogene ◽

10.1038/onc.2014.271 ◽

2014 ◽

Vol 34 (25) ◽

pp. 3264-3272 ◽

Cited By ~ 26

Author(s):

C-S Yang ◽

K Matsuura ◽

N-J Huang ◽

A C Robeson ◽

B Huang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Death ◽

Fatty Acid ◽

Cancer Cell ◽

Fatty Acid Synthase ◽

Regulatory Mechanism ◽

Ovarian Cancer Cell ◽

Cancer Cell Death ◽

Caspase 2

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Diallyl Sulfide-Mediated Modulation of the Fatty Acid Synthase (FASN) Leads to Cancer Cell Death in BaP-Induced Lung Carcinogenesis in Swiss Mice

Journal of Inflammation Research ◽

10.2147/jir.s284279 ◽

2020 ◽

Vol Volume 13 ◽

pp. 1075-1087

Author(s):

Arif Khan ◽

Fahad A Alhumaydhi ◽

Ameen SS Alwashmi ◽

Khaled S Allemailem ◽

Mohammed A Alsahli ◽

...

Keyword(s):

Cell Death ◽

Fatty Acid ◽

Cancer Cell ◽

Fatty Acid Synthase ◽

Lung Carcinogenesis ◽

Diallyl Sulfide ◽

Swiss Mice ◽

Cancer Cell Death

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

Cell Death and Disease ◽

10.1038/s41419-021-04262-x ◽

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.

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Targeted Depletion of Amino Acids As a Novel Therapy for Acute Leukemia and Other Cancers: Mechanisms and Countermechanisms

Blood ◽

10.1182/blood.v128.22.4716.4716 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4716-4716 ◽

Cited By ~ 2

Author(s):

Aysenur Esen ◽

Anwar A Khan ◽

Jason Chan ◽

Nadim Mahmud ◽

John G. Quigley

Keyword(s):

Amino Acids ◽

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Stress Responses ◽

Drug Combination ◽

Metabolic Reprogramming ◽

Low Doses ◽

Cancer Cell Death ◽

Mtorc1 Pathway

Abstract Introduction: Metabolic reprogramming by cancer cells to allow proliferation and survival suggests targeting of relatively cancer cell-specific metabolic processes as a potential cancer therapy. The amino acid (aa) glutamine (GLN) functions as an exchange factor to facilitate cell import of essential amino acids (EAA), which positively regulate translation by the mTORC1 pathway (via phosphorylation of S70K and 4EBP1), allowing proliferation. Most cancer cells also rely on GLN, rather than glucose for citric acid cycle (TCA) anaplerosis, and as a source of energy, anti-oxidants and components for protein synthesis. L-asparaginase (L-Ase), an enzyme that breaks down extracellular asparagine (ASN, the least prevalent intracellular aa), is used in the treatment of ALL. L-Ase is also glutaminolytic, resulting in GLN depletion and apoptosis that is suppressed by ASN repletion, which modulates the cell stress responses (ISR, upregulatingATF4, CHOP, aa transporters, and asparagine synthetase (ASNS)). Thus, (i) ASN is a critical signal preventing cell death from GLN depletion; (ii) ASN repletion (via ASNS) may be the important function of GLN within cancer cells, and (iii) mechanisms that deplete bothkey aa may be synergistic in implementing cancer cell death Apart from non-EAA synthesis and aa uptake (#1 in Fig. 1A), there are two major pathways of cellular aa repletion: (i) autophagy, a process whereby damaged proteins are delivered to the lysosome for degradation (#2), and (ii) the ubiquitin-proteasome system (UPS, #3), which also degrades damaged or misfolded cell proteins, allowing aa recycling. Notably, UPS inhibition significantly decreases ASN (andcystine) levels. The aim of our studies is to explore mechanisms of depleting intracellular GLN and ASN levels in cancer cells, firstinvestigating the potential synergistic effects of combining L-Ase, with Chloroquine (CQ, autophagy inhibition) and Bortezomib (BTZ, proteasome inhibition), and then analyzing cancer cell counter mechanisms. Results: We performed kill-curves with individual drugs, and then combinations of L-ase, CQ and BTZ in REH (ALL) cells. Notably, inhibitory effects on aarepletion pathways, as determined by western blot analysis of cell lysates at 12h (Fig. 1B), were seen with a combination of significantly lowered doses of each drug [BTZ 2nM (40% of LD50); L-Ase 0.2IU (15%); CQ 100mM (50%)]. The mTORC1 pathway is especially susceptible to inhibition by drug combination-mediated aa depletion (decreased phosphorylation of 4EBP1 and S6K1; compare lanes 2-4 & 5-8), while autophagy (monitored by increasing levels of LC3-II) is also inhibited. Cell viability was assessed after 48h. Although the low doses of each drug used has a minimal impact on viability (range 75-130% of control), the combination above (2nM;0.2IU;100mM) results in synergistic cell death [55% (n = 1)]. We will examine further the effects of this drug combination on normal CD34+ cells, prior to studies of efficacy inxeno-transplant models. Most tumors are metabolically flexible, e.g., they can use glucose if deprived of GLN to replenish TCA, and, via TCA intermediates, increase GLN levels, and thereby ASN, via pyruvate carboxylase (PC), transaminases (GOT1, 2), glutaminesynthetases(GDH, GS) and ASNS (see Fig. 1 pathways). Thus, we interrogated, byqPCR, potentially relevant pathways that may be used to evade glutamine and asparagine depletion-induced apoptosis (Fig. 1C). Of 12 genes tested, GLN deprivation significantlyupregulatesGLS1, GOT1, and ASNS to increase ASN levels, while the ISR is activated (CHOP), and SLC7A11, a cysteine importer upregulated in tumors (for glutathione production) is also significantly upregulated. Preliminary studies of REH and A549 (lung cancer) cells suggest a common theme in metabolic responses to GLN depletion in diverse cancer cells is ASN synthesis through GOT1 and ASNS upregulation, and likely ROS production throughcystineuptake. Conclusions: Commonly, inhibition of one metabolic pathway results in upregulation of another. Our studies indicate that combination therapy, using low doses of available, well-studied drugs depletes keyaa ASN and GLN, and prevents their repletion, causing cancer cell death. In addition, our studies of the cellular responses to GLN depletion alone indicate additional targets that should be considered to prevent ASN-mediated inhibition of cell death in diverse cancer types. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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A synthetic lethal drug combination mimics glucose deprivation–induced cancer cell death in the presence of glucose

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011471 ◽

2019 ◽

Vol 295 (5) ◽

pp. 1350-1365 ◽

Cited By ~ 3

Author(s):

James H. Joly ◽

Alireza Delfarah ◽

Philip S. Phung ◽

Sydney Parrish ◽

Nicholas A. Graham

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Drug Combination ◽

Glucose Transporter ◽

Glucose Deprivation ◽

Metabolic Reprogramming ◽

Synthetic Lethal ◽

Cancer Cell Death

Metabolic reprogramming in cancer cells can increase their dependence on metabolic substrates such as glucose. As such, the vulnerability of cancer cells to glucose deprivation creates an attractive opportunity for therapeutic intervention. Because it is not possible to starve tumors of glucose in vivo, here we sought to identify the mechanisms in glucose deprivation–induced cancer cell death and then designed inhibitor combinations to mimic glucose deprivation–induced cell death. Using metabolomic profiling, we found that cells undergoing glucose deprivation–induced cell death exhibited dramatic accumulation of intracellular l-cysteine and its oxidized dimer, l-cystine, and depletion of the antioxidant GSH. Building on this observation, we show that glucose deprivation–induced cell death is driven not by the lack of glucose, but rather by l-cystine import. Following glucose deprivation, the import of l-cystine and its subsequent reduction to l-cysteine depleted both NADPH and GSH pools, thereby allowing toxic accumulation of reactive oxygen species. Consistent with this model, we found that the glutamate/cystine antiporter (xCT) is required for increased sensitivity to glucose deprivation. We searched for glycolytic enzymes whose expression is essential for the survival of cancer cells with high xCT expression and identified glucose transporter type 1 (GLUT1). Testing a drug combination that co-targeted GLUT1 and GSH synthesis, we found that this combination induces synthetic lethal cell death in high xCT-expressing cell lines susceptible to glucose deprivation. These results indicate that co-targeting GLUT1 and GSH synthesis may offer a potential therapeutic approach for targeting tumors dependent on glucose for survival.

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