Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy. Increased lipid uptake, storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. Lipids constitute the basic structure of membranes and also function as signaling molecules and energy sources. Sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors in the endoplasmic reticulum, play a central role in the regulation of lipid metabolism. Recent studies have revealed that SREBPs are highly up-regulated in various cancers and promote tumor growth. SREBP cleavage-activating protein is a key transporter in the trafficking and activation of SREBPs as well as a critical glucose sensor, thus linking glucose metabolism and de novo lipid synthesis. Targeting altered lipid metabolic pathways has become a promising anti-cancer strategy. This review summarizes recent progress in our understanding of lipid metabolism regulation in malignancy, and highlights potential molecular targets and their inhibitors for cancer treatment.

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Lipid metabolism reprogramming and its potential targets in cancer

Cancer remains the second leading cause of mortality worldwide. In the course of this multistage and multifactorial disease, a set of alterations takes place, with genetic and environmental factors modulating tumorigenesis and disease progression. Metabolic alterations of tumors are well-recognized and are considered as one of the hallmarks of cancer. Cancer cells adapt their metabolic competences in order to efficiently supply their novel demands of energy to sustain cell proliferation and metastasis. At present, there is a growing interest in understanding the metabolic switch that occurs during tumorigenesis. Together with the Warburg effect and the increased glutaminolysis, lipid metabolism has emerged as essential for tumor development and progression. Indeed, several investigations have demonstrated the consequences of lipid metabolism alterations in cell migration, invasion, and angiogenesis, three basic steps occurring during metastasis. In addition, obesity and associated metabolic alterations have been shown to augment the risk of cancer and to worsen its prognosis. Consequently, an extensive collection of tumorigenic steps has been shown to be modulated by lipid metabolism, not only affecting the growth of primary tumors, but also mediating progression and metastasis. Besides, key enzymes involved in lipid-metabolic pathways have been associated with cancer survival and have been proposed as prognosis biomarkers of cancer. In this review, we will analyze the impact of obesity and related tumor microenviroment alterations as modifiable risk factors in cancer, focusing on the lipid alterations co-occurring during tumorigenesis. The value of precision technologies and its application to target lipid metabolism in cancer will also be discussed. The degree to which lipid alterations, together with current therapies and intake of specific dietary components, affect risk of cancer is now under investigation, and innovative therapeutic or preventive applications must be explored.

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Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment.

Lung cancer is the leading cause of cancer death in the world and there is no current treatment able to efficiently treat the disease as the tumor is often diagnosed at an advanced stage. Moreover, cancer cells are often resistant or acquire resistance to the treatment. Further knowledge of the mechanisms driving lung tumorigenesis, aggressiveness, metastasization, and resistance to treatments could provide new tools for detecting the disease at an earlier stage and for a better response to therapy. In this scenario, Yes Associated Protein (YAP) and Trascriptional Coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as promising therapeutic targets. Here, we will discuss the most recent advances made in YAP and TAZ biology in lung cancer and, more importantly, on the newly discovered mechanisms of YAP and TAZ inhibition in lung cancer as well as their clinical implications.

YAP and TAZ in Lung Cancer: Oncogenic Role and Clinical Targeting

Loss of tumor suppressor liver kinase B1 (LKB1) promotes cancer cell proliferation but also leads to decreased metabolic plasticity in dealing with energy crises. Autophagy is a protective process involving self-cannibalization to maintain cellular energy homeostasis during nutrient deprivation. We developed a mouse model for Lkb1-deficient lung cancer with conditional deletion of essential autophagy gene Atg7 to test whether autophagy compensates for LKB1 loss for tumor cells to survive energy crises. We found that autophagy ablation was synthetically lethal during Lkb1-deficient lung tumorigenesis in both tumor initiation and tumor growth. We further found that autophagy deficiency causes defective intracellular recycling, which limits amino acids to support mitochondrial energy production in starved cancer cells and causes autophagy-deficient cells to be more dependent on fatty acid oxidation (FAO) for energy production, leading to reduced lipid reserve and energy crisis. Our findings strongly suggest that autophagy inhibition could be a strategy for treating LKB1-deficient lung tumors.

/pdf/autophagy-modulates-lipid-metabolism-to-maintain-metabolic-pppftmcm13.pdf

Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis

Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune-associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mco2.27

Lipid metabolism in cancer progression and therapeutic strategies

Lung cancer is currently one of the most serious health issues in developed and developing countries. There are multiple available treatment options; however survival still remains very poor. Despite metabolism alteration being one of the hallmarks described in human cancer, lipid metabolism disorders are less known. They are recently becoming more important in this setting and therefore achieving a deeper knowledge might be helpful to obtain new strategies to accurate diagnosis, estimate prognosis, and develop therapeutic agents based on bioactive compounds such as cerulenin, SCD1, ACLY inhibitors, statins, polyphenolic compounds, etc. The present paper reviews the basis of lipid metabolism in lung cancer and suggests potential biomarkers. Further investigation is crucial to improve our knowledge in this area.

Ruth Sánchez Martínez

Papers

Lipid metabolism and lung cancer.

Erratum to "Lipid metabolism and lung cancer" [Crit. Rev. Oncol. Hematol. 112, April (2017), 31-40].