Introduction to De Novo Fatty Acid Synthesis in Cancer
De novo fatty acid synthesis is a metabolic pathway that allows cells to produce fatty acids from scratch. In the context of cancer, this pathway is often upregulated, providing rapidly proliferating cancer cells with essential building blocks for membrane biosynthesis, energy storage, and signaling molecules. Understanding the role of de novo fatty acid synthesis in cancer can offer insights into potential therapeutic targets.
What is De Novo Fatty Acid Synthesis?
De novo fatty acid synthesis is the process by which cells create fatty acids from acetyl-CoA and malonyl-CoA, primarily in the cytosol, using ATP and NADPH. This process is catalyzed by the enzyme complex
Fatty Acid Synthase (FASN), which is often found to be overexpressed in various cancers.
Why is De Novo Fatty Acid Synthesis Upregulated in Cancer?
Cancer cells have high energetic and biosynthetic demands due to their rapid proliferation. Upregulation of de novo fatty acid synthesis provides cancer cells with a steady supply of lipids necessary for synthesizing membranes, signaling molecules, and energy storage.
Oncogenes like MYC and signaling pathways such as
PI3K/AKT/mTOR often drive the increased expression and activity of FASN, facilitating this metabolic reprogramming.
How Does De Novo Fatty Acid Synthesis Contribute to Tumor Growth?
The fatty acids synthesized de novo are crucial for building cell membranes, producing lipid-based signaling molecules, and storing energy in the form of triglycerides. This lipid supply supports the structural and functional demands of rapidly dividing tumor cells. Furthermore, certain fatty acids can modulate the tumor microenvironment, promoting cancer cell survival, proliferation, and metastasis.
What are the Potential Therapeutic Targets in This Pathway?
Targeting de novo fatty acid synthesis presents a promising therapeutic strategy. Inhibitors of FASN, like
Orlistat and
TVB-2640, have shown potential in preclinical and some early-phase clinical trials. These inhibitors aim to disrupt the lipid biosynthesis essential for tumor growth, leading to reduced cancer cell viability and proliferation.
Are There Side Effects Associated with Inhibiting Fatty Acid Synthesis?
While targeting fatty acid synthesis can inhibit tumor growth, it may also affect normal cells that require fatty acids for physiological functions. Side effects could include weight loss, liver dysfunction, and neuropathy. Therefore, strategies to selectively target cancer cells or to combine these inhibitors with other therapies are under investigation to minimize adverse effects.
How Does De Novo Fatty Acid Synthesis Interact with Other Metabolic Pathways in Cancer?
De novo fatty acid synthesis is intricately linked with other metabolic pathways like glycolysis and the
pentose phosphate pathway. These pathways provide the necessary ATP and NADPH and are also often upregulated in cancer. The interplay between these pathways supports the anabolic growth of tumors, creating opportunities for multi-targeted therapeutic interventions.
What Role Does De Novo Fatty Acid Synthesis Play in Cancer Resistance?
Cancer cells can develop resistance to therapies by altering their metabolic pathways. Enhanced de novo fatty acid synthesis can contribute to resistance against chemotherapeutic agents by providing energy and building blocks that support repair and survival mechanisms. Understanding these adaptations can help in designing combination therapies that prevent or overcome resistance.
Conclusion
De novo fatty acid synthesis is a critical metabolic adaptation in cancer, supporting various cellular processes essential for tumor growth and survival. By elucidating the mechanisms and interactions of this pathway, researchers can develop targeted therapies that potentially inhibit cancer progression with reduced side effects. Future research directions include exploring combination therapies and precision medicine approaches to exploit the vulnerabilities in cancer metabolism effectively.
