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Jan 11, 2024
Lung cancer stands as one of the most common and challenging malignant tumors worldwide, with its complex metabolic reprogramming mechanisms, particularly in lipid metabolism, continually challenging existing medical treatments. This article delves deep into the fatty acid metabolism processes within lung cancer cells, revealing their pivotal role in tumor progression and exploring how targeting these processes can develop new therapeutic strategies. As molecular targeted therapies and immunotherapies evolve, understanding how to effectively tackle the energy needs and metabolic adaptability of lung cancer cells becomes increasingly vital. Through this article, we will explore the roles of fatty acid uptake, synthesis, storage, and oxidation in lung cancer, and how they influence tumor growth and spread, with the ultimate goal of providing more precise and effective treatment options for patients.
1. What is Fatty Acid Uptake in Lung Cancer Mechanism
1.1 How Does CD36 Function in Lung Cancer Fatty Acid Absorption?
1.2 What Role Does FABP Play in Lung Cancer's Lipid Metabolism?
1.3 Impact of FFAR in Lung Cancer: Understanding Free Fatty Acid Receptors
2. What is the Process of Fatty Acid Synthesis in Lung Cancer?
2.1 ACLY's Role in Lung Cancer: Connecting Metabolism and Therapy
2.2 Understanding ACC in Lung Cancer Fatty Acid Synthesis
2.3 The Critical Role of FASN in Lung Cancer Development
2.4 SCD1's Influence on Lipid Metabolism in Lung Cancer Cells
3. Mechanisms of Fatty Acid Storage and Release in Lung Cancer
4. Exploring Fatty Acid Oxidation's Impact in Lung Cancer Progression
5.Therapeutic Targeting of Fatty Acid Metabolism in Lung Cancer
Lung cancer is one of the most common malignant tumors globally, with inconspicuous early symptoms leading to the diagnosis of most patients at an advanced stage. Despite significant improvements in patient prognosis with the emergence of molecular targeted therapy and immunotherapy, drug resistance and adverse reactions continue to affect treatment efficacy. Metabolic reprogramming is a hallmark of malignant tumors, mainly involving enhanced glycolysis, active glutamine metabolism, and abnormal lipid metabolism. However, past studies on lung cancer metabolism have focused primarily on glycolysis, with relatively less research on lipid metabolism.
In recent years, the importance of lipid metabolism, especially fatty acid metabolism reprogramming, in lung cancer development has become increasingly recognized. Fatty acids are essential for building cell membranes and providing energy, while also maintaining cellular balance. Enhanced fatty acid metabolism in lung cancer cells plays a critical role in its progression. This paper focuses on exploring potential molecular targeted therapies for lung cancer by analyzing key enzymes and proteins involved in fatty acid metabolism reprogramming.
Tissue cells primarily uptake exogenous free fatty acids from the microenvironment to support biosynthesis and energy production. This external uptake of fatty acids relies on specialized transport proteins such as CD36, the family of fatty acid transport proteins (FATP), and fatty acid-binding proteins (FABP). These proteins are often highly expressed in tumor cells, which may be an adaptive response to the low oxygen and low pH environment. For instance, under hypoxic conditions, tumor cells induce the expression of FABP3 and FABP7 via hypoxia-inducible factor-1α (HIF-1α). In acidic environments, tumor cells promote CD36 expression in a transforming growth factor-β (TGF-β)-dependent manner to enhance fatty acid uptake and form lipid droplets, thus facilitating tumor metastasis. The increased dependency of tumors on exogenous fatty acid uptake makes fatty acid uptake metabolism a potential therapeutic target for lung cancer.
CD36, also known as fatty acid translocase, is a member of the scavenger receptor family, primarily involved in lipid uptake, immune recognition, and cell adhesion processes. The expression levels of CD36 vary at different stages of tumor development, with higher expression often observed in metastatic lesions compared to primary tumors, suggesting an important role for CD36 in the process of tumor metastasis. Additionally, CD36 expression levels are associated with treatment resistance, such as upregulation of CD36 in lapatinib-resistant breast cancer cells, and targeting CD36 can restore sensitivity to lapatinib. However, the role of CD36 in non-small cell lung cancer (NSCLC) remains unclear.
FABP is a group of low molecular weight proteins consisting of 12 family members, serving as lipid chaperones to facilitate the transport of fatty acids into organelles such as mitochondria, peroxisomes, and the nucleus. Ovarian cancer metastasis promotes lipolysis in adjacent adipocytes by upregulating FABP4 expression and uptaking the released fatty acids from adipocytes. Inhibition of FABP4 expression restricts ovarian cancer metastasis. Similarly, a study exploring the expression and significance of FABP5 in NSCLC found that metastatic lesions exhibit significantly higher levels of FABP5 expression compared to primary lesions. However, the expression levels of FABP5 in lymph node metastatic lesions are similar to those in primary lesions, suggesting that FABP5 may be associated with distant metastasis in lung cancer.
The FFARs that have been extensively studied include FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120, and FFAR1/GPR40. The former two can be activated by short-chain free fatty acids, while the latter two are primarily activated by medium and long-chain free fatty acids. Free fatty acids, as natural ligands of FFARs, bind to the corresponding extracellular components of the receptors, activating them. This leads to the dissociation of the alpha subunit of the heterotrimeric G protein and the beta-gamma subunit, further affecting intracellular signaling proteins, and participating in various cellular physiological and pathological processes. Previous research on FFARs has mainly focused on metabolic diseases such as type 2 diabetes and obesity. Synthetic ligands for FFAR4, such as TUG-891, have been considered potential therapeutic drugs for these diseases. In recent years, many studies have shown that activation or inhibition of FFARs can affect the growth of tumor cells in breast cancer, prostate cancer, colon cancer, ovarian cancer, and other tumors. However, the exact role of FFARs in the occurrence and development of tumors remains to be further studied.
The substrate for fatty acid synthesis is acetyl-CoA generated by ATP-citrate lyase (ACLY) catalyzing the cleavage of citrate. Acetyl-CoA undergoes carboxylation by acetyl-CoA carboxylase (ACC) and condensation by fatty acid synthase (FASN) to produce palmitic acid. Palmitic acid is further elongated by the enzyme elongase of very long chain fatty acids (ELOVL) and desaturated by stearyl coenzyme A desaturase 1 (SCD1), resulting in fatty acids with varying carbon chain lengths and degrees of saturation, participating in various biological processes such as membrane synthesis and signal transduction. In normal tissues, de novo fatty acid synthesis is restricted to adipocytes and hepatocytes. However, to meet their high metabolic demands and adapt to the reduced serum-derived fatty acids in the tumor microenvironment, tumor cells upregulate the expression of enzymes involved in fatty acid synthesis. Therefore, enhanced fatty acid synthesis metabolism is considered a significant hallmark of tumors.
The expression of enzymes related to fatty acid synthesis is mainly regulated by sterol-regulatory element-binding proteins (SREBPs) at the transcriptional level. SREBPs serve as crucial links between various oncogenic pathways and lipid metabolism. Thus, targeting SREBPs may represent a potential effective strategy to enhance the efficacy of targeted gene therapies in cancer treatment.
ACLY is considered a crucial enzyme linking glucose and glutamine metabolism with fatty acid synthesis, catalyzing the breakdown of citrate to generate acetyl-CoA within the cytoplasm. Transcription of ACLY is regulated by SREBP1, and its activity can be directly activated by phosphorylation by AKT. In lung cancer tissues, ACLY activity is significantly higher than in normal lung tissues, and ACLY expression levels are important predictors of poor prognosis in NSCLC. Inhibition of ACLY leads to growth arrest in lung cancer cells. Acetyl-CoA generated by ACLY not only serves as a substrate for fatty acid synthesis but also supports protein acetylation, particularly of histones. A study exploring the impact of ACLY on the stemness characteristics of hepatocellular carcinoma found that ACLY stabilizes β-catenin by promoting its acetylation, thereby regulating the Wnt signaling pathway to maintain the stemness characteristics of hepatocellular carcinoma. It is evident that ACLY occupies a central position in cellular metabolism, linking synthetic metabolism, catabolic metabolism, and histone acetylation. Therefore, targeting ACLY may represent an effective anti-tumor therapeutic strategy.
ACC catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, which is the rate-limiting step in fatty acid synthesis. In the human genome, there are two isoforms of ACC: ACC1, primarily expressed in adipocytes and hepatocytes, involved in fatty acid synthesis and associated with tumorigenesis and development; ACC2, mainly expressed in cardiac and skeletal muscle cells, generates malonyl-CoA to inhibit the rate of fatty acid β-oxidation via CPT1. The activity of ACC is regulated by AMPK. Under energy stress conditions such as glucose deprivation, tumor cells experience impaired pentose phosphate pathway, resulting in reduced production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is often consumed in fatty acid synthesis. This triggers AMPK to phosphorylate and inhibit ACC, thereby blocking fatty acid synthesis. Concurrently, the reduction in malonyl-CoA, a product of ACC, weakens its inhibitory effect on the rate-limiting enzyme of fatty acid β-oxidation, CPT1, leading to enhanced fatty acid oxidation metabolism. Targeting ACC can inhibit fatty acid synthesis while increasing fatty acid oxidation metabolism, thereby exacerbating fatty acid depletion in tumor cells and inhibiting tumor growth.
FASN utilizes NADPH as a reducing equivalent to catalyze the consecutive condensation reaction between acetyl-CoA and malonyl-CoA, forming palmitic acid. It is upregulated in most human tumors, including lung cancer, and is often associated with poor prognosis. Additionally, the saturated fatty acids synthesized by FASN can disrupt the distribution of certain receptors on the cell membrane surface by affecting membrane fluidity and lipid raft formation, thereby inducing drug resistance.
SCD1 catalyzes the formation of Δ9 double bonds in saturated fatty acids (such as stearic acid and palmitic acid), producing monounsaturated fatty acids (such as oleic acid and palmitoleic acid). However, SCD1 requires the presence of NADPH and oxygen to function. Tumor cells upregulate the expression of fatty acid uptake-related proteins and SCD1 under hypoxic conditions. In vitro lipid depletion conditions, inhibiting SCD1 can lead to an imbalance in the ratio of saturated to unsaturated fatty acids within cells. Excessive saturated fatty acids can induce lipotoxicity and endoplasmic reticulum stress, leading to tumor cell apoptosis, which can be reversed by exogenously adding unsaturated fatty acids. Therefore, high expression of SCD1 in lung cancer is often associated with poor prognosis in patients. Studies have shown that EGFR can stabilize SCD1 by phosphorylating the Y55 site of SCD1, thereby upregulating the synthesis of monounsaturated fatty acids (MUFA) in lung cancer cells and promoting lung cancer growth.
In times of cellular nutrient abundance, excess fatty acids within cells are esterified into inert triacylglycerols, accumulating within the phospholipid bilayer of the endoplasmic reticulum. Upon surpassing a certain threshold, they separate from the endoplasmic reticulum via budding to form lipid droplets. Lipid droplets are considered as specialized intracellular organelles primarily involved in maintaining lipid homeostasis and storing energy. Tumor cells rich in lipid droplets often exhibit increased resistance to chemotherapy. Studies suggest that employing Raman imaging technology to assess lipid droplet content could serve as a novel tool for predicting drug responses in cancer patients.
During energy stress, fatty acids are primarily released via lipolysis of lipid droplets, wherein triacylglycerols are hydrolyzed into fatty acids and glycerol by adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MAGL). MAGL, in particular, catalyzes the hydrolysis of the endocannabinoid system agonist 2-AG to influence tumor growth. Furthermore, the expression of MAGL in the tumor microenvironment also impacts tumor progression.
Long-chain acyl-CoA synthetase (ACSL) converts fatty acids into fatty acyl-CoA, which is then transported into the mitochondria with the assistance of CPT1 for β-oxidation. The resulting acetyl-CoA undergoes the tricarboxylic acid cycle and oxidative phosphorylation to generate ATP, providing energy for tumor cells. Enzymes associated with fatty acid oxidation (FAO) are upregulated in various tumor tissues. For instance, lung cancer cells upregulate ACSL expression via the oncogene KRAS, while breast cancer stem cells enhance FAO by upregulating transcriptional expression of CPT1 through the Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway to maintain their survival advantage.
CPT1 is the rate-limiting enzyme in fatty acid oxidation, consisting of three subtypes: CPT1A, CPT1B, and CPT1C, with CPT1A being the most widely distributed. CPT1A plays a crucial role in tumor metastasis.
Multiple studies have indicated that fatty acid metabolism in lung cancer cells significantly influences the progression of tumors. Therefore, exploiting the differential reliance on fatty acid metabolism between normal and tumor tissues, disrupting the fatty acid metabolism pathways in lung cancer cells to disrupt lipid homeostasis, may represent a novel therapeutic approach for inhibiting lung cancer growth.
In recent years, inhibitors targeting enzymes involved in fatty acid synthesis metabolism have gradually gained attention, with some drugs progressing to clinical trial stages and showing promising application prospects. Among them, FASN is the most extensively studied enzyme in fatty acid metabolism. Preclinical studies have shown that inhibiting FASN can suppress lung cancer growth without affecting normal cells, providing a therapeutic window for anti-tumor treatment.
Although preclinical studies have suggested that ACLY inhibitors (such as SB-204900 and ETC1002) have anti-tumor effects, clinical research on ACLY inhibitors primarily focuses on lipid-related disorders and lacks reports on clinical trials for lung cancer treatment. This may be due to the requirement of higher drug concentrations to completely inhibit ACLY activity. Drug combination therapy may be a feasible solution to this dilemma.
Inhibiting tumor cell SCD1 (MF-438) can disrupt the desaturation of fatty acids, disturb the lipid metabolism homeostasis within tumor cells, and promote lung cancer cell apoptosis through inducing cell cycle arrest, activating endoplasmic reticulum stress, among other mechanisms. Targeting SCD1 has shown promising results in various preclinical studies on tumors. However, in lung cancer cells, SCD1 is not the sole desaturase responsible for converting palmitic acid into monounsaturated fatty acids. When SCD1 is inhibited, lung cancer cells can bypass SCD1 and activate fatty acid desaturase 2 (FADS2) to desaturate palmitic acid into oleic acid to support membrane synthesis during proliferation, suggesting that combination therapy with SCD1 and FADS2 inhibitors is needed to block the desaturation pathway in lung cancer cells.
Tumors often compensate by externally acquiring unsaturated fatty acids. Therefore, besides inhibiting enzymes involved in fatty acid synthesis, regulating the content and types of fatty acids in the diet can also enhance the efficacy of anti-tumor therapy. Research indicates that calorie restriction (limiting daily caloric intake without causing malnutrition) can restrict the exogenous uptake of fatty acids by reducing plasma lipid levels. Calorie restriction combined with SCD1 enzyme inhibitors disrupts endogenous fatty acid synthesis in tumor cells and can inhibit the growth of pancreatic cancer.
Tumor metabolism shows adaptability, so targeting single molecules in fatty acid metabolism doesn't provide a long-lasting anti-cancer effect. Currently, these inhibitors mainly act as supplementary treatments to strengthen existing anti-cancer therapies. Moreover, when targeting fatty acid metabolism, it's crucial to choose reliable targets to enhance lung cancer treatment effectiveness while minimizing any negative effects on normal cell metabolism.
Lung cancer regulates the expression of enzymes and receptors involved in fatty acid metabolism to enhance lipid processing within tumor cells, sustaining proliferation, promoting metastasis, and inducing resistance to treatment. Inhibiting enzymes associated with fatty acid synthesis such as FASN, ACLY, and SCD, along with dietary adjustments, disrupts the lipid metabolism equilibrium within lung cancer cells, thereby inhibiting proliferation and metastasis. However, applying these strategies clinically presents challenges, given the tumor's metabolic adaptability and potential off-target effects of drugs. Addressing these issues requires further clarification of the relationship between fatty acid metabolism and the onset and progression of lung cancer, identification of more therapeutic targets, maximizing the anti-tumor potential of targeting fatty acid metabolism, developing highly specific small molecule targeted drugs, and optimizing clinical treatment strategies based on tumor metabolic dependencies.
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