Lipid metabolism in cancer: A systematic review

Wafa Khan¹, Dominic Augustine¹, Roopa S Rao¹, Shankargouda Patil², Kamran Habib Awan³, Samudrala Venkatesiah Sowmya¹, Vanishri C Haragannavar¹, Kavitha Prasad^4
1 Department of Oral Pathology and Microbiology, M.S. Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India
² Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Jazan University, Jazan, Saudi Arabia
³ College of Dental Medicine, Roseman University of Health Sciences, South Jordan, Utah, United States
⁴ Department of Oral and Maxillofacial Surgery, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India

Correspondence Address:
Dominic Augustine
Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, M.S. Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru – 560 054, Karnataka
India.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcar.JCar_15_20

Abstract

Preclinical studies and clinical trials have emphasized the decisive role of lipid metabolism in tumor proliferation and metastasis. This systematic review aimed to explore the existing literature to evaluate the role and significance of the genes and pathways most commonly involved in the regulation of lipid metabolism in cancer. The literature search was performed as per Preferred Reporting Items for Systematic Reviews and Meta-analyses. Approximately 2396 research articles were initially selected, of which 215 were identified as potentially relevant for abstract review. Upon further scrutiny, 62 of the 215 studies were reviews, seminars, or presentations, and 44 were original study articles and were thus included in the systematic review. The predominant gene involved in lipid metabolism in cancer was stearoyl-coenzyme A desaturase 1 (SCD1), followed by fatty acid synthase (FASN). The pathway most commonly involved in lipid metabolism in cancer was the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway, followed by the mitogen activated protein kinase (MAPK) pathway. SCD1 and FASN play significant roles in the initiation and progression of cancer and represent attractive targets for potentially effective anti-cancer treatment strategies. The regulation of cancer metabolism by the Akt kinases will be an interesting topic of future study.

Keywords: Akt, fatty acid synthase, lipid metabolism, oral cancer, PI3K, signaling pathways, stearoyl-coenzyme A desaturase.

Introduction

Cancer is the leading cause of death in economically developed countries.^[1] Total cancer deaths are projected to increase from 7.1 million in 2002 to 11.5 million in 2030.^[2] The burden of cancer is alarming in economically flourishing countries due to population growth and the adoption of lifestyle choices associated with an increased risk of cancer, such as smoking, physical inactivity, and processed diets.^[3] Cancers arise from the accumulation of genetic and epigenetic changes and abnormalities in cancer-associated signaling pathways.^[4] Metabolic reprogramming, a major hallmark of cancer, provides cancer cells with both energy and various metabolites vital for maintaining their aberrant survival and growth. Metabolism generates oxygen radicals, which contribute to oncogenic mutations.^[5] Lipids are among these vital metabolites; lipid metabolism is a multistep process involving several key enzymes and is suggested to generate the building blocks of many cells and organelles. Moreover, lipids play important roles as second messengers and hormones.^[6] Lipid metabolism is regulated by multiple signaling pathways and generates a variety of bioactive lipid molecules. An increase in lipid metabolism is a remarkable feature of cancer metabolism, deregulation of or abnormalities in these signaling pathways might result in abnormal cell proliferation and growth. Physiological processes such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, motility, membrane homeostasis, response to chemotherapy, and drug resistance are regulated by lipid metabolism.^[7] Understanding the genes and pathways most commonly involved in lipid metabolism in cancer could help provide evidence for elucidating the mechanisms of cancer cell death and potentially help in the discovery of potential cancer therapeutic targets. This systematic review aimed to study the existing literature to evaluate the role and significance of the genes and pathways most commonly involved in the regulation of lipid metabolism in cancer.

The following key question was constructed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines: “Do the genes and pathways associated with lipid metabolism play a significant role in cancer progression?”

Materials and Methods

This systematic review was written according to PRISMA. Prospero databases were searched for any registered protocol on similar topic, no title related to or resembling the current title was found.

Inclusion criteria

The articles included in the study were full-length, English language articles that focused on basic research on genes and associated signaling pathways involved in lipid metabolism in cancer.

Exclusion criteria

The exclusion criteria were articles on topics other than lipid metabolism as an etiological factor in cancer; studies that lacked proper validation of their results; articles other than original research, such as reviews, editorial letters, books, and abstracts; and studies with insufficient data.

Data sources and search strategy for literature on lipid metabolism in cancer

Databases such as PubMed, Google Scholar, Scopus, EBSCO, E-Journals and Science Direct were searched using key words such as “genes in lipid metabolism of cancer,” “pathways in lipid metabolism of cancer” and “biomarkers in lipid metabolism of cancer.” PubMed searches were also performed for references cited in review articles on lipid metabolism in cancer. Articles published until October 2017 were included. References of the selected articles were again screened for additional relevant studies that could have gone undetected during the electronic search.

Data collection

The data collection was performed in two phases. Initially, the articles were evaluated as a whole, and we listed the various genes and their role in cancer. The second phase included an evaluation of the different techniques used and an assessment of the validation of the results in each article. The overall data collection form was used to obtain the following information from the individual articles: Authors, Journal in which the article was published, Year of publication, Research focus, Methodologies employed, Results obtained, Conclusions and Future scope of research in the given field.

Synthesis of results

The results of the individual studies were then summarized, and the various genes involved in lipid metabolism in cancer were entered on a list. Data on the same genes were grouped and analyzed. Individual points of interest across the selected studies were summarized.

Results

Search results
Upon conducting a search with the abovementioned key words, 2396 search results were identified. However, these results included seminars, conference presentations, letters to editors, short communications, journal publications, and books. Among these 2396 results, 80 articles were identified as potentially relevant. The title and abstract of these articles were reviewed. 62 articles that fit the inclusion criteria were selected and further reviewed by two researchers for reliability. In cases of disagreement, a third reviewer was consulted. Among the 62 articles, 18 were excluded for the following reasons: articles on topics other than lipid metabolism as an etiological factor in cancer; studies that lacked proper validation of their results; articles other than original research, such as reviews, editorial letters, books, and abstracts; studies with insufficient data; and articles published before 2009. A total of 44 articles were selected for the systematic review by the reviewers [Figure 1].^{[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49]}

Figure 1: Selection of articles represented by Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart Click here to view

Study results
A total of 44 articles were selected by the reviewers. The selected original research articles focus on lipid metabolism in cancer progression, as shown in [Table 1].

Table 1: Summary of the selected articles Click here to view

A total of 38 genes were found to be involved in lipid metabolism in cancer progression, as shown in [Table 2]. The most commonly involved gene was stearoyl-coenzyme A desaturase 1 (SCD1),^{[15],[18],[19],[20],[21],[23],[24],[27],[30],[32],[33],[34],[35],[39],[40],[42],[43],[44],[46],[49]} followed by followed by fatty acid synthase (FASN), which was identified in 7 studies.^{[12],[25],[26],[29],[41],[45],[48]} Fatty acid binding protein 4 (FABP4) was described in 5 studies.^{[8],[14],[22],[25],[37]}

Table 2: Genes involved in lipid metabolism of cancer Click here to view

[Table 3] depicts the most common metabolic pathways implicated in cancer progression. Eight metabolic signaling pathways responsible for cancer progression were identified. Among these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was the most commonly implicated in cancer development and progression,^{[8],[12],[14],[19],[26],[27],[32],[41],[46],[47]} followed by the mitogen activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) pathways (MAPK pathway;^{[7],[22],[32],[47]} and mTOR pathway:^{[12],[19],[27],[33]}).

Table 3: Lipogenic genes and their metabolic pathways Click here to view

[Table 4] shows the various lipogenic inhibitors that could be used as therapeutic drugs to suppress the activity of a gene product in the tumor. The most commonly reported inhibitor was TOFA (5 tetradecyl oxy 2 furoic acid).^{[42],[50],[51]}

Table 4: Lipogenic genes and their inhibitors Click here to view

Discussion

Cancer cells usually display aberrant cellular metabolism that directly contributes to tumorigenicity and malignancy. The main abnormality is aerobic glycolysis. Metabolic alterations are highly associated with mutations in oncogenes and tumor suppressor genes that play an important role in cancer development and progression. Increased lipid synthesis is one of the most significant metabolic aberrations in cancer cells. Lipids are considered the building blocks of cell membranes during cell proliferation and also function as signaling molecules. Recent discoveries on the impact of indispensable lipid enzymes in cancer progression have extended our knowledge of lipid metabolism and its impact on tumor etiology.^[13] The activation of oncogenes and the loss of tumor suppressor genes contribute to metabolic reprogramming in cancer, which subsequently results in enhanced uptake of nutrients to further supply biosynthetic pathways.^[52] It is important to identify the genes involved in lipid metabolism, as they will provide numerous avenues for confirming the impact of targeting the associated pathways in cancer.

The most commonly involved genes in lipid metabolism in cancer

The most commonly reported gene involved in lipid metabolism in cancer was SCD1, followed by FASN and FABP4.

Stearoyl-coenzyme A desaturase 1

SCDs are mainly localized in the endoplasmic reticulum and are also known as fatty acyl-CoA delta-9 desaturases. SCD1 is a crucial regulator of the fatty acid composition of cellular lipids. To generate monounsaturated fatty acids (MUFAs), SCD1 catalyzes the formation of a double bond at the ninth positions of palmitic acid and stearic acid.^[30] In human tissue, there are two SCDs, SCD1, and SCD5. SCD1 expression is sensitive to fatty acids and carbohydrates, and it is regulated by hormones and various growth factors. SCD5, another variant of SCD, was recently found to be present in higher amounts in the human brain, pancreas and embryonic tissue; however, its biological role remains uncharacterized.^[53] SCD1 is known to play a significant role in many human cancers, such as breast, lung, hepatocellular, prostate, and clear cell carcinoma, depicted in [Figure 2]. Several cancer cells and tissues have abnormal high levels of Monounsaturated fatty acids (MUFA) in major glycerolipids. High SCD1 levels act as a chief cofactor in creating metabolic disturbances or aberrancies that favor oncogenic processes. The presence of abnormally increased levels of SCD1 in various types of cancer cells provides initial evidence that this enzyme may be functionally connected to the onset and progression of cancer.^[53] TNM stage, tumor grade, and lymphatic metastasis have been positively correlated with SCD1 expression in various studies. SCD1 knockdown inhibits various tumor cells that depend on the reduction of synthesized fatty acids and regulates the AKT-mTOR pathway. Thus, SCD1 could be a prognostic indicator of cancer severity.^[13] A study by von Roemeling et al.^[21] found that SCD1 may be a prognostic biomarker. SCD1 expression has been shown to be upregulated in numerous neoplastic lesions, including adenocarcinoma and gastric, breast, prostate, ovarian, and colon cancer. Thus, SCD1 has been suggested as a molecular target in several tumor types, including clear cell renal carcinoma, and may be a prognostic biomarker. A study performed by Bansal et al.^[32] showed that in the United States and Europe, the incidence of hepatocellular carcinoma is increasing more rapidly in younger generations. The authors demonstrated that SCD1 plays a significant role in the biosynthesis of MUFAs. SCD1 acts as an essential regulator and is expressed at high levels in multiple human hepatocellular cancer cell lines. The authors also discovered that when these cell lines were treated with a set of chemotherapeutics, SCD1 gene expression increased. Moreover, a correlation was identified between increased enzyme expression and the degree of tumor differentiation.

Figure 2: Regulation of stearoyl-coenzyme A desaturase 1 a key regulator of lipid biosynthesis in cancer cells Click here to view

SCDs also play a critical role in the biosynthesis of saturated fatty acids (SFAs) and MUFAs. A number of reactions occur in cancer cells to support the continuous synthesis of SFAs and MUFAs; these reactions involve enzymes such as adenosine triphosphate-citrate lyase, acetyl-CoA carboxylase (ACC), FAS, and SCD.^[53] Any alterations in these enzymes disturb the balance of SFAs and MUFAs within the cell and drastically alters the cellular functions of SFAs and MUFAs. In particular, MUFAs play a vital role in the regulation of cell proliferation and programmed cell death. SCD1 shares a common molecular link with various pathological disorders that have been associated with cancer. According to the literature review, major events could be involved in the upregulation of SCD in various human cancers, for example, regulation of the rate of fatty acid biosynthesis, the generation of MUFAs for lipid macromolecule formation, and alterations in signaling networks that maintain the expression and activity of key enzymes of lipid metabolism. SCD1 activity may facilitate the high fatty acid biosynthetic rate by modulating ACC, the key regulatory enzyme in this pathway.

Lipid biosynthetic pathways, such as the fatty acid synthesis and desaturation pathways, are the most promising molecular targets for cancer therapy. The inhibition of SCD1, the enzyme that produces MUFAs, impairs cancer cell proliferation, survival and invasiveness and dramatically reduces tumor formation. CVT-11127, C75, cerulenin, and TOFA are novel small-molecule inhibitors of SCD activity that result in SCD1 depletion, leading to reduced lipid synthesis, impaired proliferation stemming from cell cycle arrest at the G<Subscript>1</Subscript>/S transition, and the triggering of programmed cell death. These inhibitors were found to be effective at blocking SCD activity in human cancer cell lines by decreasing the rate of cell proliferation in oncogene-transformed cancer cells. A decrease in the rate of proliferation of SCD1-deficient cells indicated that SCD1 is involved in a crucial metabolic step that is common to many cancer-cell types. Genetic and pharmacological inhibition of SCD1 triggers AMPK activation and impairs de novo fatty acid synthesis from glucose. By controlling SFA levels through conversion into MUFAs, SCD1 modulates the rate of fatty acid synthesis and consequently, of overall glycerolipid biosynthesis.

Moore et al.^[44] stated that a reduction in SCD expression contributes to the development of human prostate carcinoma. Several mechanisms are possibly responsible for the reduction in SCD. Regulators of tumor cell growth have been shown to modulate SCD expression, and alterations in SCD levels influence signaling pathways important for cell growth and metabolism. SCD deficiency enhances signaling through the insulin receptor (IR) pathway, as demonstrated by an increase in basal phosphorylation of IR, IR substrate (IRS)-1 and IRS-2; increased association of IRS-1 and IRS-2 with PI3K; and increased phosphorylation of Akt.^[54] The activation of the PI3K/Akt pathway has been shown to be important for regulating the proliferation, apoptosis, and growth of many cancers, including prostate carcinoma.

Fatty acid synthase
Fatty acid synthase (FASN) is another gene that was found to be upregulated in many studies. The FASN enzyme plays an essential role in lipid synthesis. Long-chain fatty acids are produced from acetyl-CoA and malonyl-CoA. Low expression levels and activity of FASN are tightly regulated by hormones, diet and growth factors. De novo fatty acid synthesis occurs in proliferating cancer cells to provide lipids for membrane formation and energy production, as shown in [Figure 3]. FASN expression was been reported to be highly associated with oncogenic activity in several cancers, such as prostate, ovarian, breast, endometrial, thyroid, colorectal, bladder, lung, thyroid, oral, tongue, esophageal, hepatocellular, pancreatic, and gastric carcinoma. Poor prognosis and a lower survival rate have been found to be strongly associated with increased FASN expression in different cancer types. FASN plays a vital role in tumor development, progression, and survival, which has been confirmed in previous studies involving siRNA knockdown of FASN in tumors.^[29],[55] FASN is a biosynthetic enzyme that is involved in neoplastic lipogenesis. While accumulating evidence for this literature review, we found that FASN overexpression was common in many human cancers, suggesting that it is a metabolic oncogene with an important role in tumor growth and survival and thus an attractive target for cancer therapy. The regulation of FASN expression in cancer is complex.^[56]

Figure 3: Regulation of fatty acid synthase in cancer: SREBP1-c: Sterol elementary binding protein, MAPK: Mitogen-activated protein kinase, PI3 kinase: Phosphoinositide 3-kinase, Akt: Protein kinase B Click here to view

Microenvironmental stresses play a role in regulating FASN expression through growth factor receptors, such as ERBB-2 and epidermal growth factor receptor (EGFR), which interact and trigger the downstream PI3K/AKT and MAPK signaling pathways, leading to the upregulation of FASN expression. Aberrant activation of AKT and MAPK leads to FASN overexpression in hormone-sensitive organs such as the breast, ovary, and prostate through the activation of sex hormone receptors by estrogen, progesterone, and androgen.

Fatty acid binding protein 4
FABP4 has been increasingly thought to play an essential role in cancer progression. Regarding various metabolic functions, FABP4 is responsible for the conversion of various fatty acids to cellular compartments. FABP4, an adipokine, also plays an important role in numerous critical cellular processes, such as the regulation of gene expression and cell proliferation and differentiation. FABP4 has been suggested as a new prognostic indicator in bladder cancer and ovarian cancer, as well as in obese patients with breast cancer. Overexpression of FABP4 in glioblastoma acts as proangiogenic factor because FABP4 expression is regulated by VEGF. FABP4 promotes prostate cancer progression and provides an interaction point between fat cells or adipocytes in the bone marrow. Guaita-Esteruelas et al.^[14] stated that FABP4 protein could be regarded as a potential target for the treatment of different types of cancer, as it was discovered as a significant protein responsible for ovarian cancer cell migration.

Most commonly involved pathway in lipid metabolism in cancer
The most commonly involved in lipid metabolism in cancer was the PI3K/Akt signaling pathway. PI3K catalyzes the production of the lipid second messenger phosphatidylinositol-3, 4, 5-triphosphate (PIP3) at the cell membrane. Cell proliferation, survival, growth, and motility are among the various normal cellular processes controlled by the PI3K/Akt signaling pathway and are critical for tumorigenic growth.^[47] In oncogenesis, the PI3K/Akt pathway has been more widely investigated, and altered expression and abnormal mutation of this pathway have been associated with cancer. PI3K was first identified as an essential enzyme responsible for the transforming activity of oncogenes, and Akt was also explored as a viral oncogene.^{[57],[58],[59]} Akt plays a significant role in increasing glucose metabolism of cancer by modulating hexokinase, which results in efficient glucose-6-phosphate production.^[60] High glycolytic rates in cancer cells are observed when the PI3K/Akt pathway is altered.^[61] Small-molecule inhibitors of PI3K and mTOR prevent glucose uptake by tumors harboring PIK3CA mutations, and this finding correlates with tumor regression, emphasizing the role of the PI3K/Akt signaling pathway in glucose metabolism in cancer.^[62]

Regulation of stearoyl-coenzyme A desaturase 1: A key regulator of lipid biosynthesis in cancer cells
In human tissues and tumor cells, aberrant levels of MUFAs in all major glycerolipids are commonly encountered. Abnormal MUFA levels are evidence of carcinogenic processes, as has been explored in recent studies in various cellular models. Increased SCD1 activity levels are predominantly caused by the presence of abundant MUFAs. Three major mechanisms are known to regulate SCD1 activity in lipogenesis in cancer cells, and they involve substrate availability for lipid biosynthesis, metabolic control of fatty acid biosynthesis, and regulation of growth and survival signaling. Upregulated SCD1 may cause overactive lipid biosynthetic machinery in rapidly replicating cancer cells, thereby providing ideal fatty acid substrates. Moreover, SCD1 plays a vital role in promoting lipogenesis by increasing fatty acid synthesis through various mechanisms. ACC, a key enzyme, has been shown to catalyze the formation of malonyl-CoA in the fatty acid biosynthetic pathway. Abnormally high levels of SCD1 contribute to a decrease in the activity of AMP-activated protein kinase (AMPK), which mainly targets ACC for inactivation. Current results have revealed that complete activation of the Akt pathway is required to regulate SCD1 activity.^[53],[63]

Regulation of fatty acid synthase in cancer
The regulation of FASN in cancer is complex Various growth factor receptors, such as ERBB-2 and EGFR, act in concert to activate the PI3K/AKT and MAPK signaling pathways following the activation of FASN. The altered activation of AKT and MAPK occurs in hormone-sensitive organs such as the breast and prostate. The upregulation of growth factors may enhance FASN overexpression, which further activates growth factor receptor tyrosine kinases, creating an autoregulatory loop. AKT and MAPK transduction pathways are responsible for regulating FASN expression through the modulation of sterol regulatory element-binding protein (SREBP)-1c.^[55],[56]

Lipogenic inhibitors
TOFA was found to be the most common inhibitor used to suppress tumor growth. Mason et al.,^[35] identified TOFA as a potential SCD1 inhibitor by using a fatty acid strategy to describe various inhibitors of fatty acid synthesis. Guseva et al.^[50] stated that TOFA decreases fatty acid synthesis; inhibits the expression of androgen receptor (AR), neuropilin-1 and Mcl-1; and kills prostate cancer cells independent of p53 status. Li et al.^[33] reported that TOFA enhances caspase-3 activity and inhibits fatty acid synthesis by inducing the apoptosis of ovarian cancer cells.

Current perspective

In cancers such as lung, breast, and prostate cancer, lipid metabolism plays an essential role, but its role in oral cancer has not been adequately researched. Very few studies have described the role of lipid metabolism in oral cancer. Based on accumulated data, SCD1 has arisen as a crucial factor involved in cancer development and progression. SCD1 is considered a chief participant in the regulation of lipid synthesis, but its role in oral cancer has not been investigated. In the future, further investigations should be carried out on the regulation of signaling pathways, and genes involved in lipid metabolism in oral cancer with a larger sample size to provide rational targets.

Conclusion
In the present study, 38 genes involved in lipid metabolism in cancer were analyzed; among these genes, SCD1 was the most commonly reported. SCD1 is a major participant in the modulation of lipid synthesis. FASN is another gene that was found to be upregulated in many studies and is known for its significant role in lipogenesis. Akt kinase pathways are considered dynamic areas of study in the regulation of metabolism in cancer, although we have a very limited understanding of the integration of these two processes by Akt family members. SCD1 and FASN play substantial roles in the initiation and progression of cancer, these genes could possibly be attractive anti-cancer targets in the near future.

Most of the studies considered for this systematic review were conducted on cell lines and animal models, whether the same expression of proteins/genes will be obtained in human tissue requires more studies in the future on human biological samples. Increasing evidence in the literature suggests that oncoproteins have a direct effect on reprogramming cancer cell metabolism and making them addicted to certain metabolic pathways. Future investigations with a large sample size should focus on elucidating the mechanism by which signaling pathways regulate lipid metabolism. This would generate novel therapeutic strategies for the development of anti-cancer drugs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Figures
[Figure 1], [Figure 2], [Figure 3]
 

Tables
[Table 1], [Table 2], [Table 3], [Table 4]