Inhibitors of lipogenic enzymes as a potential therapy against cancer

Montesdeoca, Nicolás; López, M. Allué; Ariza, Xavier; Herrero, Laura; Makowski, Kamil

doi:10.1096/fj.202000705r

Cited by 45 publications

(24 citation statements)

References 170 publications

(491 reference statements)

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“…The most researched pharmacological targets are transmembrane receptors connected to enzymes, commonly employed in oncology and immunology [ 180 ]. Lipogenic enzyme inhibitors have also been investigated as a possible cancer treatment [ 181 ].…”

Section: Enzymes As a Special Class Of Therapeutic Targetsmentioning

confidence: 99%

The Lactate and the Lactate Dehydrogenase in Inflammatory Diseases and Major Risk Factors in COVID-19 Patients

Gupta

2022

Inflammation

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— Lactate dehydrogenase (LDH) is a terminating enzyme in the metabolic pathway of anaerobic glycolysis with end product of lactate from glucose. The lactate formation is crucial in the metabolism of glucose when oxygen is in inadequate supply. Lactate can also be formed and utilised by different cell types under fully aerobic conditions. Blood LDH is the marker enzyme, which predicts mortality in many conditions such as ARDS, serious COVID-19 and cancer patients. Lactate plays a critical role in normal physiology of humans including an energy source, a signaling molecule and a pH regulator. Depending on the pH, lactate exists as the protonated acidic form (lactic acid) at low pH or as sodium salt (sodium lactate) at basic pH. Lactate can affect the immune system and act as a signaling molecule, which can provide a “danger” signal for life. Several reports provide evidence that the serum lactate represents a chemical marker of severity of disease similar to LDH under inflammatory conditions. Since the mortality rate is much higher among COVID-19 patients, associated with high serum LDH, this article is aimed to review the LDH as a therapeutic target and lactate as potential marker for monitoring treatment response of inflammatory diseases. Finally, the review summarises various LDH inhibitors, which offer potential applications as therapeutic agents for inflammatory diseases, associated with high blood LDH. Both blood LDH and blood lactate are suggested as risk factors for the mortality of patients in serious inflammatory diseases.

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Section: Enzymes As a Special Class Of Therapeutic Targetsmentioning

confidence: 99%

The Lactate and the Lactate Dehydrogenase in Inflammatory Diseases and Major Risk Factors in COVID-19 Patients

Gupta

2022

Inflammation

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“…Interestingly, breast cancer cells are particularly dependent on fatty acid synthesis after metastasizing to the brain which has limited fatty acid availability compared to either the primary site or other metastatic sites 57 . These studies have driven efforts to target FASN and ACACA enzymes for therapeutic benefit 43,55,[58][59][60] . However, our work shows that the ability of BNIP3 to promote lipid clearance from HCC tumor cells, was not dependent on rates of lipogenesis since BNIP3 could decrease lipid levels robustly even in the presence of an effective FASN inhibitor (Fig.…”

Section: Discussionmentioning

confidence: 99%

BNIP3 attenuates hepatocellular carcinoma by promoting lipid droplet turnover at the lysosome.

Berardi

Bock-Hughes

Drake

et al. 2021

Preprint

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Hepatic steatosis is a major etiological factor in hepatocellular carcinoma (HCC). Work reported here identifies BNIP3 as a suppressor of HCC that mitigates against lipid accumulation. Loss of BNIP3 decreased tumor latency and increased tumor burden in a mouse model of HCC. This was associated with increased lipid accumulation and elevated HCC tumor cell growth. Conversely, exogenous BNIP3 decreased lipid levels and reduced HCC tumor cell growth. Mutant BNIP3W18A that is unable to promote mitophagy did not decrease HCC cell growth and was defective at reducing lipid levels. Growth suppression by BNIP3 was not mediated by effects on fatty acid oxidation (FAO) or de novo lipogenesis (DNL). Rather, BNIP3 suppressed HCC cell growth by promoting lipid droplet turnover at the lysosome through a process we have termed “mitolipophagy” in which lipid droplets and mitochondria are turned over together at the lysosome. Low BNIP3 expression in human HCC also correlated with increased lipid content and worse prognosis than HCC expressing high levels of BNIP3. This work reveals a role for BNIP3 and lipid droplet turnover at the lysosome in attenuating HCC.

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“…Endocrine-resistant MCF-7/HRG cells, which mimic a biological scenario of persistent HER2 pathway activation in luminal B-like tumors with low HER2 levels, lose their strong ability to form colonies in soft-agar under estrogen-depleted and/or anti-estrogen (tamoxifen and fulvestrant)-containing conditions in response to pharmacological blockade of FASN activity. The exact reason why FASN facilitates resistance to endocrine therapy in HRG-overexpressing, ER+/HER2− luminal B-like breast cancer cells needs to be explored in depth; however, it is clear that FASN pro-survival signaling [27,28,31] is co-opted to support the cross-talk between HRG-driven HER2/HER3 pathway activation and ER signaling, thereby enabling estrogen-independence and resistance to SERMs/SERDs (Figure 5). Importantly, in vivo treatment with the FASN inhibitor C75 notably restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, in vivo treatment with the FASN inhibitor C75 notably restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. The capacity of anti-FASN therapy to restore the sensitivity to tamoxifen and fulvestrant in MCF-7/HRG xenograft tumors certainly suggests that certain subgroups of HRG-overexpressing, ER-positive/HER2-negative patients who phenotypically behave as triple-negative breast carcinomas and are resistant to endocrine therapy could greatly benefit from adding clinical-grade FASN inhibitors [31][32][33] to combined treatments with SERMs/SERDs. Int.…”

Section: Discussionmentioning

confidence: 99%

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Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer

Menéndez

Mehmi

Papadimitropoulou

et al. 2020

IJMS

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HER2 transactivation by the HER3 ligand heregulin (HRG) promotes an endocrine-resistant phenotype in the estrogen receptor-positive (ER+) luminal-B subtype of breast cancer. The underlying biological mechanisms that link them are, however, incompletely understood. Here, we evaluated the putative role of the lipogenic enzyme fatty acid synthase (FASN) as a major cause of HRG-driven endocrine resistance in ER+/HER2-negative breast cancer cells. MCF-7 cells engineered to stably overexpress HRG (MCF-7/HRG), an in vitro model of tamoxifen/fulvestrant-resistant luminal B-like breast cancer, showed a pronounced up-regulation of FASN gene/FASN protein expression. Autocrine HRG up-regulated FASN expression via HER2 transactivation and downstream activation of PI-3K/AKT and MAPK-ERK1/2 signaling pathways. The HRG-driven FASN-overexpressing phenotype was fully prevented in MCF-7 cells expressing a structural deletion mutant of HRG that is sequestered in a cellular compartment and lacks the ability to promote endocrine-resistance in an autocrine manner. Pharmacological inhibition of FASN activity blocked the estradiol-independent and tamoxifen/fulvestrant-refractory ability of MCF-7/HRG cells to anchorage-independently grow in soft-agar. In vivo treatment with a FASN inhibitor restored the anti-tumor activity of tamoxifen and fulvestrant against fast-growing, hormone-resistant MCF-7/HRG xenograft tumors in mice. Overall, these findings implicate FASN as a key enabler for endocrine resistance in HRG+/HER2- breast cancer and highlight the therapeutic potential of FASN inhibitors for the treatment of endocrine therapy-resistant luminal-B breast cancer.

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Inhibitors of lipogenic enzymes as a potential therapy against cancer

Cited by 45 publications

References 170 publications

The Lactate and the Lactate Dehydrogenase in Inflammatory Diseases and Major Risk Factors in COVID-19 Patients

The Lactate and the Lactate Dehydrogenase in Inflammatory Diseases and Major Risk Factors in COVID-19 Patients

BNIP3 attenuates hepatocellular carcinoma by promoting lipid droplet turnover at the lysosome.

Fatty Acid Synthase Is a Key Enabler for Endocrine Resistance in Heregulin-Overexpressing Luminal B-Like Breast Cancer

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