The mTOR Inhibitor Rapamycin Synergizes with a Fatty Acid Synthase Inhibitor to Induce Cytotoxicity in ER/HER2-Positive Breast Cancer Cells

Cao, Yan; Huang, Wei; Minjuan, Zheng; Xue, Yan; Yang, Jingyue; Li, Wenchao; Han, Sheng

doi:10.1371/journal.pone.0097697

Cited by 40 publications

(30 citation statements)

References 39 publications

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“…Using non‐cancer cell models, however, both Porstmann and Duvel and their respective coworkers have convincingly shown that Akt‐mediated cell growth and enhanced lipogenesis does result from downstream activation of SREBP‐1c through the action of mTOR complex 1 (mTORC1), and that this is accompanied by nuclear translocation of the active SREBP1c fragment and the expected induction of mRNAs coding the lipogenic enzymes (Porstmann et al, ; Duvel et al, ). As anticipated from this signaling cascade, simultaneous inhibition of FASN with Cerulenin and mTOR signaling with rapamycin exerted a synergistic anticancer effect in Her2/neu‐expressing BC cells (Yan et al, ).…”

Section: Oncogenic Antigen 519mentioning

confidence: 98%

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered

Kinlaw

Baures

Lupien

et al. 2016

Journal Cellular Physiology

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Brisk fatty acid (FA) production by cancer cells is accommodated by the Warburg effect. Most breast and other cancer cell types are addicted to fatty acids (FA), which they require for membrane phospholipid synthesis, signaling purposes, and energy production. Expression of the enzymes required for FA synthesis is closely linked to each of the major classes of signaling molecules that stimulate BC cell proliferation. This review focuses on the regulation of FA synthesis in BC cells, and the impact of FA, or the lack thereof, on the tumor cell phenotype. Given growing awareness of the impact of dietary fat and obesity on BC biology, we will also examine the less-frequently considered notion that, in addition to de novo FA synthesis, the lipolytic uptake of preformed FA may also be an important mechanism of lipid acquisition. Indeed, it appears that cancer cells may exist at different points along a “lipogenic-lipolytic axis”, and FA uptake could thwart attempts to exploit the strict requirement for FA focused solely on inhibition of de novo FA synthesis. Strategies for clinically targeting FA metabolism will be discussed, and the current status of the medicinal chemistry in this area will be assessed.

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Section: Oncogenic Antigen 519mentioning

confidence: 98%

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered

Kinlaw

Baures

Lupien

et al. 2016

Journal Cellular Physiology

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“…Fatty acid metabolism is also being targeted in combination with mTOR inhibitors for cancer therapy. In pre-clinical studies of ER/HER2 positive breast cancer, cerulenin, a FASN inhibitor synergized with rapamycin to induce apoptosis and inhibit tumorigenesis [308]. FASN inhibition in ovarian cancer led to cell death, which involved a caspase 2 mechanism via the mTORC1 negative regulator REDD1 [309].…”

Section: Co-targeting Mtor and Metabolismmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

154

108

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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“…Inhibition of MAP kinase also decreases transcription from the FASN promoter and reduces FASN expression in MCF7 cells [63] . The mTOR inhibitor rapamycin may also inhibit FASN in breast cancer cells [64] . Recently, a "HER2-FASN axis" is thought to exist which indicates the bidirectional regulation mechanism between FASN and HER2.…”

Section: Metabolic Reprogramming In Breast Cancermentioning

confidence: 99%

Targeting metabolism in breast cancer: How far we can go?

Long

Zhang

2016

WJCO

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receptor-2 targeted therapy, marked a new era of breast cancer treatment. However, except for chemotherapy, an efficient drug treatment to improve the overall survival of breast cancer patients is still lacking for triple negative breast cancer. Furthermore, a certain proportion of breast cancer patients present with resistance to drug therapy, making it much more difficult to control the deterioration of the disease. Recently, altered energy metabolism has become one of the hallmarks of cancer, including breast cancer, and it may be linked to drug resistance. Targeting cellular metabolism is becoming a promising strategy to overcome drug resistance in cancer therapy. This review discusses metabolic reprogramming in breast cancer and the possible complex mechanism of modulation. We also summarize the recent advances in metabolic therapy targeted glycolysis, glutaminolysis and fatty acids synthesis in breast cancer. Core tip: Breast cancer cells display distinct metabolic characteristics according to different molecular phe notypes. There may be crosstalk with the estrogen receptor and human epidermal growth factor receptor2 signal pathways in the metabolic regulation in breast cancer cells that make it more complex to evaluate the efficiency of an antimetabolic drug. On the other hand, the research on target metabolism in breast cancer will also largely help us to understand the complicated mechanism by which an antimetabolic drug impro ves the efficacy of cancer therapy or overcomes drug resistance. AbstractAdjuvant therapies for breast cancer have achieved great success in recent years and early breast cancer is now a curable or chronic disease. Targeted therapies, including endocrine therapy and human epidermal growth factor MINIREVIEWS 122February 10, 2016|Volume 7|Issue 1|

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The mTOR Inhibitor Rapamycin Synergizes with a Fatty Acid Synthase Inhibitor to Induce Cytotoxicity in ER/HER2-Positive Breast Cancer Cells

Cited by 40 publications

References 39 publications

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Targeting metabolism in breast cancer: How far we can go?

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