Metastasis is one of the important characteristics of malignant tumors and is also the main cause of tumor-related deaths. Tumor metastasis is a complex multi-step process regulated by various factors, including interactions between tumor cells themselves and the tumor microenvironment. It involves at least four steps: the highly invasive tumor cells escaping from the primary site, circulating through the bloodstream or lymphatic system via immune evasion, surviving and successfully establishing growth in the microenvironment of the target organ, and eventually forming distant metastatic lesions. The regulation of tumor metastasis involves multiple factors, such as the tumor cells themselves and their interactions with the microenvironment. The mechanisms underlying tumor metastasis regulation have not been fully elucidated.
Metabolic reprogramming is also an important feature of tumors, as tumor cells adapt their metabolism to meet the demands of increased biosynthesis and rapid proliferation. Existing research has shown that metabolic reprogramming plays a critical role in the occurrence and development of tumors by regulating tumor invasion and metastasis potential, maintaining the stemness of tumor stem cells, and modulating the tumor microenvironment. Acetyl-CoA, an important metabolic intermediate in cells, determines the balance between catabolic and anabolic metabolism, and connects the metabolic processes of various important molecules such as glucose, lipids, and proteins. On one hand, acetyl-CoA serves as the initial metabolite of the tricarboxylic acid cycle and the starting metabolite for lipid synthesis. On the other hand, acetyl-CoA can also influence gene expression through its impact on histone acetylation, an epigenetic mechanism. The intracellular level of acetyl-CoA is known to be closely associated with important biological processes such as cell proliferation, programmed cell death, and autophagy.
Invasion and metastasis are the main biological characteristics of malignant tumors. Tumor metastasis is a complex multi-step process that primarily involves tumor cells detaching from the primary site, invading and infiltrating the surrounding stroma by crossing the basement membrane, entering the circulatory system and surviving as circulating tumor cells, obstructing and extravasating through the vascular wall to form micro-metastatic colonies in distant tissue stroma, and eventually establishing clinically detectable metastatic lesions through colonization in target organs. The pathways of tumor metastasis mainly include hematogenous metastasis, lymphatic metastasis, and implantation metastasis. This article mainly discusses the impact and mechanisms of acetyl-CoA metabolism on the invasive and metastatic abilities of tumor cells, specifically the process of tumor cells detaching from the primary site.
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Abnormal Accumulation of Acetyl-CoA in Tumors
Numerous tumor forms exhibit metabolic reprogramming of acetyl-CoA, according to studies. There is an aberrant buildup of acetyl-CoA in tumor cells as evidenced by the high expression or enhanced activity of several important enzymes involved in acetyl-CoA production and metabolism, including ACLY, ACC1, ACSS1, and ACSS2. The buildup of acetyl-CoA has been shown to be intimately linked to the spread of liver cancer, and studies have demonstrated that the amount of acetyl-CoA is higher in liver cancer tissue.
Transcriptional and post-translational regulation of acetyl coenzyme A (acetyl-CoA) metabolic enzymes in normal cells (Guertin et al., 2023).
Acetyl-CoA Metabolism Regulates Epithelial-Mesenchymal Transition (EMT) in Tumor Cells
An essential cellular mechanism involved in tumor invasion and metastasis is epithelial-mesenchymal transition (EMT). EMT causes tumor cells to lose some epithelial cell traits and acquire certain mesenchymal cell traits, resulting in malignant phenotypes including decreased cell adhesion and increased cell motility. Snail, Slug, Twist, and Zebl are a few of the transcription factors that predominantly control EMT.
Nuclear/cytosolic Acetyl-CoA Metabolism Enzymes and EMT
ACC1 is a rate-limiting enzyme in de novo fatty acid synthesis, catalyzing the conversion of acetyl-CoA to malonyl-CoA. Studies on breast cancer have found that leptin and transforming growth factor beta 1 (TGF-β1) can phosphorylate ACC1 via the TAK-AMPK pathway, inhibiting its function. This leads to an increase in nuclear/cytosolic acetyl-CoA levels and acetylation levels of the transcription factor Smad2, promoting EMT in breast cancer cells and ultimately facilitating breast cancer metastasis and recurrence. ACSS2 is predominantly involved in acetyl-CoA synthesis from acetate in the nuclear/cytosolic compartments and plays a dominant role in various malignant primary tumors and metastatic tumors.
ACOT12 is mainly expressed in the cytoplasm of human liver cells and catalyzes the hydrolysis of acetyl-CoA into acetate and CoA. Functionally, ACOT12 inhibits liver cancer metastasis. Downregulation of ACOT12 can increase cellular acetyl-CoA levels and histone acetylation levels, thereby promoting EMT in liver cancer cells by epigenetically activating the expression of TWIST2.
Mitochondrial Acetyl-CoA Metabolism Enzymes and EMT
The pyruvate dehydrogenase complex (PDC) primarily exists in the mitochondria and catalyzes the conversion of pyruvate to acetyl-CoA. Pyruvate dehydrogenase kinase (PDK) can phosphorylate and inactivate mitochondrial PDC.
Many tumor cells rely on aerobic glycolysis instead of oxidative phosphorylation for sustained proliferation and survival. Myc and HIF-1 have been implicated in upregulating the gene expression of PDK to promote this metabolic switch. Additionally, under the stimulation of growth signals such as epidermal growth factor (EGF) or heat shock proteins (Hsp70), PDC can translocate from the mitochondria to the nucleus, catalyzing the conversion of pyruvate to acetyl-CoA and increasing histone acetylation levels. This process is crucial for cell entry into the S phase. However, direct experimental evidence regarding whether mitochondrial acetyl-CoA metabolism affects EMT in tumors is lacking and requires further investigation.
Metabolites modulate the tumor metastasis cascade (Wei et al., 2020).
Acetyl-CoA Metabolism Regulates Tumor Cell Adhesion and Migration
ACLY-dependent acetyl coenzyme A promotes tumor invasive migration through activation of Ca2+-activated T cell nuclear factor signaling
ACLY is a key enzyme that catalyzes the production of nuclear/cytosolic acetyl-CoA. It not only connects glycolysis with de novo fatty acid synthesis metabolism but also integrates metabolism with histone acetylation. ACLY plays an important role in tumor progression and metastasis. Several studies have shown that ACLY is upregulated in various types of tumors and is mainly activated by the PI3K/Akt pathway.
Acetyl-CoA activates Ca2+/calmodulin-dependent protein kinase II (CaMKII) to promote tumor invasion and metastasis.
CaMKII is a multifunctional serine/threonine protein kinase family that plays a crucial role in multiple cellular processes. Free CoA can bind to the calmodulin-binding domain (CaMBD) of CaMKII and activate it, especially at basal cellular Ca2+ concentrations. Activated CaMKII can phosphorylate serine 135 (S135) of caspase 2, inhibiting cell apoptosis and maintaining cell survival, such as in oocytes. Acetyl-CoA metabolism can enhance the metastatic potential of prostate cancer cells through the acetyl-CoA-CaMKII signaling pathway.
Acetyl-CoA Metabolism and Tumor Stem Cells
Tumor tissues contain a population of cells known as cancer stem cells (CSCs), which possess pluripotent characteristics similar to normal stem cells. These CSCs exhibit enhanced self-renewal, clonal growth, metastatic potential, homing, and proliferative abilities, thereby sustaining tumor progression. Early studies have found that ketone bodies can enhance the stemness of breast cancer cells and promote breast cancer recurrence and metastasis. Researchers speculated that ketone bodies may act through the generation of acetyl-CoA and subsequent epigenetic regulation of gene expression. Subsequent studies have shown significant changes in the level of acetyl-CoA during early embryonic development. Another study discovered that acetyl-CoA derived from glycolysis can maintain the stemness of pluripotent stem cells (PSCs) by promoting histone acetylation. These findings suggest that acetyl-CoA metabolism may play an important role in regulating tumor stem cells, but the specific regulatory mechanisms and effects of acetyl-CoA metabolism on tumor stemness require further investigation.
Acetyl-CoA metabolism is closely associated with tumor metastasis. The abnormal accumulation of acetyl-CoA in tumor cells not only provides raw materials for the synthetic metabolism of tumor cells but more importantly, it can activate the expression of specific genes or signaling pathways related to metastasis by modulating protein acetylation modifications. This, in turn, promotes tumor metastasis. These research findings suggest that acetyl-CoA may serve as an important metabolite promoting tumor metastasis.
References
- Guertin, David A., and Kathryn E. Wellen. "Acetyl-CoA metabolism in cancer." Nature Reviews Cancer 23.3 (2023): 156-172.
- Wei, Qinyao, et al. "Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications." Oncogene 39.39 (2020): 6139-6156.
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