, Fan Zhang 1,*,†1 Department of Breast and Thyroid Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, 401147 Chongqing, China
†These authors contributed equally.
Academic Editor: Graham Pawelec
Abstract
Fatty acid metabolism has attracted extensive attention for its key role in the
occurrence and development of tumors. Fatty acids not only participate in the
biosynthesis of phospholipids in the membrane to overcome the demand for rapidly
proliferating membrane lipids but also provide ATP, signaling molecules, and
NADPH through
Keywords
- fatty acid β-oxidation
- tumor
- ATP
- NADPH
- review
Tumor tissue is characterized by a microenvironment of hypoxia and low nutrients. Tumor cells undergo metabolic reprogramming to adapt to severe living conditions. “Metabolic reprogramming” has been recognized as one of the 10 markers of cancer [1]. In the last century, Otto Warburg, a German biologist, first described that compared with nonproliferating normal cells, tumor cells tend to choose to rapidly produce ATP by enhancing the conversion of glucose to pyruvate even when oxygen is sufficient [2]. Although the Warburg effect has been widely accepted as a common feature of metabolic reprogramming, increasing evidence has shown that tumor metabolic reprogramming is reflected not only in aerobic glycolysis, in which fatty acid metabolic reprogramming targeting tumor cells has gradually become the focus of tumor research. However, clinical research on tumor metabolism, especially fatty acid metabolism, failed to keep pace with the progress of basic research [3].
According to the length of the carbon chain, fatty acids (FAs) were divided into
short-chain, medium-chain, and long-chain fatty acids. FAs play an important role
in all stages of tumors [4, 5]. Generally, rapidly proliferating cells need a
large number of fatty acids to promote membrane synthesis and form phospholipids
to support replication. Simultaneously, fatty acids act as substrates for
mitochondrial ATP synthesis [6], to regulate post-translational lipid
modification and the function of signaling proteins [7, 8]. In conclusion, fatty
acids show an important effect in tumors, and interfering with fatty acid
metabolism may become a potential strategy for tumor treatment. Targeting fatty
acid metabolism reprogramming of tumor cells has gradually become the focus of
research [9]. Most of the current studies have focused on the therapeutic targets
of de novo fatty acid synthesis and on FAs uptake to limit its use as a source of
energy and cell membrane phospholipids [10, 11]. However, some studies have found
that fatty acid
Although mitochondrial FAO is the main source of bioenergy, it is not generally considered a part of the cancer metabolic blueprint. However, in the past few years, people’s views on the relationship between FAO and tumors have changed. The proliferation, survival, stemness, drug resistance, and metastasis of cancer cells depend on FAO. FAO is also reprogrammed in cancer-related immune cells and other stromal cells, which may contribute to the immunosuppressive tumor microenvironment. FAO is the transformation of long-chain fatty acids into acetyl-CoA through the process of fatty acid activation, fatty acid transport and fatty acid oxidation under the action of a series of enzymes. The whole process produces a large number of reducing agents and ATP, which is more efficient than the tricarboxylic acid cycle. Recently, studies have provided vital evidence that cancer has a “Lipolytic phenotype” [14]. Similar to glycolysis or fatty acid synthesis in tumors, FAO shows abnormalities in a variety of tumors [15, 16, 17].
Some studies demonstrated that the expression of
In addition, FAO produces a large amount of ATP, which provides the possibility for rapid tumor proliferation, invasion, and metastasis. Simultaneously, as one of the main sources of NADPH, the role of balancing ROS, maintaining redox balance, and promoting tumor cell survival cannot be ignored [30]. Moreover, a variety of intermediates are produced in the process of FAO as signal molecules or raw materials for the synthesis of other important substances, providing potential conditions for tumor progression [31]. FAO affects various aspects of cancer, including proliferation, metastasis, stemness, and the immune microenvironment (Fig. 1). The exploration of targeted FAO in tumor treatment is full of great potential and possibility.
Fig. 1.Fatty acid
In the presence of ATP, CoA-SH and Mg
Fig. 2.Fatty acid
Long-chain fatty acyl-CoA synthetases (ACSLs) are a group of rate-limiting
enzymes in fatty acid metabolism that catalyze the biotransformation of exogenous
or de novo FAs to fatty acyl-CoA. The mammalian ACSLs family contains five
members, including ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6. Studies have suggested
that abnormally active ACSLs are conducive to the proliferation, migration, and
invasion of tumor cells [36]. Studies have shown that protein 1 containing the
CUB structure, as a driving factor for a variety of tumor migrations and
invasions, interacts with ACSLs family members to reduce lipid droplet abundance,
stimulate FAO and provide power for driving tumor metastasis [37]. Some studies
demonstrated that knockdown of ACSL1 inhibited the proliferation, migration, and
cell cycle of prostate cancer cells and showed a tumor inhibitory effect
in vivo [38]. Inhibition of ACSL1 could significantly interfere with
LPS-mediated downstream pathways, including P38-MAPK-MEK1/2, ERK, JNK, and
NK-
Carnitine palmitoyl transferase1 (CPT1), which is located in the outer mitochondrial membrane, is the FAO rate-limiting enzyme. It catalyzes acyl-CoA into acylcarnitine to transport fatty acids to mitochondria for further oxidation [47]. The CPT1 family consists of three subtypes: CPT1A, CPT1B, and CPT1C. CPT1C is mainly expressed in the brain [48], and an atypical isomer of CPT1. Some studies have proposed that CPTC may be a potential oncogene. The author found that the abnormal expression of CPT1C in cancer cells can promote the FAO process, promote ATP production, rescue cells from metabolic pressure, and produce resistance to mTORC1 inhibitors [49, 50, 51]. CPT1A and CPT1B are widely distributed in human organs. Compared with CPT1B, CPT1A is the key enzyme that determines the rate of FAO [52], which is more critical. CPT1A has been found to be associated with the development of a variety of tumors, such as prostate cancer, lymphocytic leukemia, and breast cancer [53, 54]. The expression of CPT1A is enhanced in recurrent breast cancer. The use of FAO inhibitors or knockout of CPT1A to block the FAO process can inhibit radiation-induced ERK activation and the invasive growth and radioresistance of radiation-resistant breast cancer cells. Other studies have shown that excessive CPT1A plays a key role in stress adaptation and antioxidant defense in prostate cancer cells [55].
In colorectal cancer cells, CPT1A-mediated elimination of reactive oxygen species (ROS) is essential for cell survival. Colorectal cancer cells with CPT1A knockdown cannot maintain the NADPH/NADP+ ratio and GSH/GSSG ratio, as well as higher intracellular ROS levels. Studies have pointed out that CPT1A-mediated FAO removal of excessive ROS from tumor cells is essential for cell survival [56]. Research on drugs regulating CPT1 has been conducted for decades but have mainly focused on type 2 diabetes, obesity, cardiovascular disease, etc. [57, 58]. In recent years, researchers have gradually realized the correlation between CPT1 and tumor progression. CPT1/2 inhibitors, as fatty acid metabolism regulators, have gradually developed into a new class of drugs, mainly malonyl-CoA analogs, glycidyl acid derivatives, and substrate inhibitors, providing new possibilities for tumor treatment [59]. With the development of research, the important role of CPT1B in cancer has been gradually recognized. Data from human breast cancer sources indicate that the STAT3-CPT1B-FAO pathway can promote the dry and chemical resistance of cancer cells. Blocking CPT1B expression will sensitize tumor cells to chemotherapy and inhibit tumor stem cells in mouse mammary tumors [60]. At present, fundamental research and clinical studies are targeting CPT1, providing powerful evidence to demonstrate the great potential of CPT1 in tumor therapy.
The first step of FAO is catalyzed by acyl-CoA dehydrogenase (ACAD), which is a
family of mitochondrial enzymes with different substrate specificities, including
very-long-chain (VLCAD) and long-chain (LCAD), medium-chain (MCAD) and
short-chain (SCAD) CoA dehydrogenase. Studies have shown that HIF-1
FAO auxiliary enzyme, 2,4-dienoyl CoA reductase 1 (DECR1) is the rate-limiting
enzyme for the oxidation of polyunsaturated fatty acids (PUFAs). Studies have
shown that it is overexpressed in a variety of tumor tissues and has a certain
relationship with the survival and prognosis of patients [3]. Knockdown of DECR1
blocked the
Changes in tumor cell metabolic patterns inevitably affect cell redox homeostasis [64]. In most cases, the growth and survival potential of tumor cells is limited by the level of NADPH in cells. On the one hand, it provides redox ability to counteract oxidative stress; on the other hand, it is a coenzyme of anabolic enzymes to maintain cell growth and proliferation. During the occurrence and development of tumors, the level of intracellular ROS increases significantly [65]. Reduced glutathione is an important antioxidant in cells that counteracts the oxidative pressure brought by ROS. In tumor cells with elevated ROS levels, reduced glutathione could be oxidized to oxidized glutathione, followed by glutathione reductase and reduced NADPH. It is reduced again under the action of to maintain the redox balance in tumor cells [66, 67].
In addition to providing energy, FAO is also an important source of NADPH [68]. Numerous studies have shown that NADPH derived from FAO in tumor cells is a key factor in counteracting oxidative stress [14, 69, 70]. Acetyl-CoA produced by FAO entered tricarboxylic acid (TCA) cycle and generated citric acids with oxaloacetic acid. Citric acids were shuttled to the cytoplasm to generate NADPH [69] (Fig. 3). Previous studies have pointed out that the main purpose of FAO in rapidly proliferating endothelial cells is to carry out de novo dNTP synthesis. Compared with resting endothelial cells, the upregulation of FAO was three times or more higher than that of proliferating endothelial cells. Its main purpose is to maintain the tricarboxylic acid cycle through NADPH regeneration to maintain redox homeostasis [71]. Considering the adverse effects of a large number of ROS, cancer stem cell-like cells maintain ROS levels by coupling FOXM1-dependent PRX3 expression and fatty acid oxidation [30]. FAO was inhibited in glioma cells and showed a significant decrease in NADPH levels, resulting in an increase in ROS levels and cell death [70]. Nissm Hay et al. [72] also demonstrated the correlation between FAO and NADPH homeostasis. Nrf2, a transcription factor that regulates cellular redox status, has been shown to promote FAO and increase NADPH regeneration, thereby guiding metabolic reprogramming during stress [73]. FAO is an important component of metabolic reprogramming by providing ATP and maintaining redox balance to promote tumor progression.
Fig. 3.FAO provides ATP and NADPH to promote tumor progression. On the one hand, NADH and FADH2 produced in the process of FAO could generate ATP through the electron transport chain (ETC). On the other hand, its metabolite acetyl-CoA enters the tricarboxylic acid (TCA) cycle to synthesize citric acid with oxaloacetic acid. Citric acid enters the cytoplasm through the citric acid shuttle to generate isocitrate. Under the action of isocitrate dehydrogenase (IDH), cytoplasmic NADPH is generated.
A variety of cells constitute a complex tumor microenvironment, including immune cells and stromal cells. Therefore, we should take the tumor as a whole into consideration. In addition to tumor cells, the existence, phenotype and function of other cells affect the progression of tumors, and the functional phenotype of these cells is closely related to their metabolic mode [74, 75]. Studies have shown that effector CD4+ T cells rely on glycolysis to provide energy and substances for biosynthesis. However, immunosuppressive T cells (Tregs) suggest a higher level of FAO [76]. Tregs combine glycolysis, fatty acid synthesis, oxidation, and other metabolic modes to defeat T cells that mainly rely on glycolysis to meet energy and material needs [77]. Several research groups have reported that M2 macrophages use FAO to promote mitochondrial oxidative phosphorylation, providing a survival advantage over M0 and M1 macrophages [78, 79]. Inhibition of FAO could prevent macrophages from polarizing to the M2 type [80]. Early studies have shown abnormal lipid accumulation in tumor-associated dendritic cells with a tolerance phenotype [81]. We investigated and summarized the role of FAO in different immune cells in the early stage and found that active FAO can cause a variety of immune cells, such as macrophages, dendritic cells, and NK cells, to change into an immune tolerance phenotype and contribute to the immunosuppressive microenvironment [82].
The dynamic crosstalk between stromal cells and tumor cells is also one of the potential mechanisms of malignant tumor progression. Adipocytes are an important component of the tumor microenvironment. Adipocytes in the tumor microenvironment secrete a large number of exosomes. These exosomes are absorbed by tumor cells, which lead to increased migration and invasion. Interestingly, it was found that the vesicles secreted by these adipocytes were rich in FAO-related proteins, which was one of their highly specific characteristics [83]. Further studies showed that in the presence of these exosomes, FAO in melanoma cells was also mobilized and became more active [83]. In addition to the abnormal FAO of adipocytes in the tumor microenvironment, studies have found that cancer related-fibroblasts actively oxidized FA and conducted minimal glycolysis by upregulating CPT1A to promote the proliferation, migration, and invasion of colon cancer cells [84]. Etomoxir directly blocks CPT1A-mediated FAO in fibroblasts, which could inhibit migration and invasion in vitro and reduce tumor growth and peritoneal metastasis in vivo [84].
Abnormally active FAO is one of the characteristics of carcinoma, which is a
prerequisite for some tumors. Some studies have shown that FAO is the driving
force of
FAO was also regulated by multiple oncogenes or tumor suppressor genes (Table 1)
[43, 61, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98]. c-Myc upregulated the main FAs production regulator sterol
regulatory element binding protein 1 (SREBP1) in tumor cells and promoted the
production of fatty acids and the process of FAO [43]. Meanwhile, c-Myc has also
been shown to regulate FAO by inhibiting the expression of ACC2, and ACC2
suppressed the effect of CPT1A through targeting malonyl-CoA [87]. Significantly,
Cyclin D1 is a cyclin, which is abnormally expressed in tumors as an oncogene.
Studiese have evaluated that it not only play a key role in the process of cell
cycle, but also inhibit the activity of PPAR
| Type | Key Genes | Specific functions |
| oncogenes | ||
| KRAS | Mutant KRAS | |
| c-Myc | c-Myc | |
| PPAR |
PPAR | |
| CD147 | CD147 | |
| CCAT1 | CCAT1 | |
| Cyclin D1 | Cyclin D1 | |
| SIK | SIK/GNAS/PKA pathway | |
| PLA2 | PLA2 mobilizes free fatty acids to maintain FAO | |
| HIF-1 |
HIF-1 | |
| AMPK | AMPK/PGC-1 | |
| Tumor suppressor genes | P53 | Mutant p53 |
| NDRG2 | NDRG2 | |
| RARRES1 | RARRES1 | |
| REDD1 | REDD1 | |
| PPAR | ||
At present, FAO and related regulatory genes as targets have been gradually
recognized and tried as potential candidates for cancer therapy. The promising
drugs (and related targets) targeting FAO in cancer mainly focused on CPT [101],
we organized the main targeted drugs (Table 2 and Fig. 4). Among them, etomoxir
plays an important role in the treatment of various tumors by targeting FAO.
Etomoxir irreversibly inhibited CPT1A and CPT1B [102]. Etomoxir significantly
reduced liver and lung metastatic nodules of colorectal cancer cells by promoting
anoikis [56]. However, etomoxir has serious side effects. Long-term use of
etomoxir could lead to cardiac hypertrophy by promoting oxidative stress and
NF-
| Agent | Target | Tumor type and mechanism | Risks |
| Etomoxir | CPT1A and CPT1B | Colorectal cancer: CPT1 |
High liver transaminase level, cardiac hypertrophy |
| Leukemia: FAO | |||
| Nasopharyngeal: PGC1 | |||
| Glioblastoma: NADPH | |||
| Breast cancer: JAK/STAT3 | |||
| Ovarian cancer: CPT1 | |||
| Prostate cancer: CPT | |||
| ST1326 | CPT1A | Leukemia: CPT1A |
Hepatotoxicity |
| Perhexiline | CPT1 and CPT2 | Breast cancer: JAK/STAT3 |
Transient effects: Predominantly are dizziness, headache, and nausea |
| Ovarian cancer: CPT1A |
Long term side effects: Hepatotoxicity and neurotoxicity | ||
| Leukemia: CPT |
|||
| HCC: CPT |
|||
| Prostate cancer: CPT |
|||
| Ranolazine | FAO/3-KAT | Breast cancer: FAO |
Excessive product can cause dizziness, nausea, vomiting, diplopia, paresthesia, confusion and loss of delayed consciousness |
| Prostate cancer: FAO | |||
| 6-gingerol | CPT-1/FASN | Colorectal cancer: FASN |
nausea, stomachache |
| FASN-overproduction of malonyl-CoA | |||
| CPT1A, carnitine acyltransferases 1A; CPT1B, carnitine acyltransferases 1B;
CPT1, carnitine acyltransferases 1; CPT2, carnitine acyltransferases 2; 3-KAT,
3-ketoacyl CoA thiolase; FASN, fatty acid synthetase; PGC1 | |||
Fig. 4.The mechanism of drugs targeting FAO in cancers. CPT in FAO as
an important target in tumor therapy. There are also potential targets for
In addition to above drugs, several potential FAO-related targeted drugs are in
the experimental stage. Chemical inhibition of ACSLs activity by triacsin C
(inhibits ACSL1, ACSL3, and ACSL4, but not ACSL5 or ACSL6) induces apoptosis in
lung, colon, and brain cancer cells [110]. 2-bromopalmitate (2-BP) is an
irreversible inhibitor of many membrane-associated enzymes. Reported as an
inhibitor of
Notably, polyunsaturated fatty acids (PUFAs) have been shown to play a vital
role in tumor treatment. According to the position and function of double bonds,
PUFAs are divided into
In addition to the effect for tumor complications, recent researches have
pointed that PUFAs also paly a vital role in suppression of tumor, including
breast cancer, colorectal cancer, liver cancer. The influence of PUFAs on tumor
could be summarized as follows: (1) Inhibition of tumor cell cycle. DHA disturbed
cell cycle by suppressing DNA synthesis in liver cancer cells and melanoma cells
[116]. Furhter, Istfan NW demonstrated the duration of S phase of tumor cells
increased significantly when
FAO plays an extremely important role in supporting tumor progression. Research
on FAO has great potential in the diagnosis and treatment of tumors. This review
focused on the key enzymes that may be used as tumor treatment targets in the
process of fatty acid
At present, FAO inhibitors have been used in the clinic, but they are mainly used to treat heart disease [132, 133, 134]. Their application in tumors is still in preclinical research or encounters bottlenecks, such as drug toxicity, and the in vivo effect is not as good as the in vitro effect. On the other hand, FAO has been proven to be indirectly activated by PPAR activators [133], AMPK activators [72], or ACC inhibitors [135], so there are indirect strategies for these targets, but the various pathways activated by these methods complicate the interpretation of the results. Therefore, further. direct targeting of FAO has great significance and potential.
FA, fatty acids; FAO, fatty acid
HC and FZ designed the research study. HC performed the research. MT and YS provided help and advice on. ZY and SY analyzed the data. HC wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
Not applicable.
We apologize to colleagues whose work is not cited due to space constraints. And we also thank anonymous reviewers for excellent criticism of the article and all the authors in the reference list.
This research was funded by Natural Science Foundation of Chongqing, China, grant number cstc2020jcyj-msxmX0485 and Medical Science and Technology Innovation Fund of Chongqing General Hospital, grant number 2019ZDXM01 and Y2020ZDXM08.
The authors declare no conflict of interest.