Abstract
Cancer cells need excess energy and essential nutrients/metabolites not only to divide and proliferate but also to migrate and invade distant organs for metastasis. Fatty acid and cholesterol synthesis, considered a hallmark of cancer for anabolism and membrane biogenesis, requires citrate. We review here potential pathways in which citrate is synthesized and/or supplied to cancer cells and the impact of extracellular citrate on cancer cell metabolism and growth. Cancer cells employ different mechanisms to support mitochondrial activity and citrate synthesis when some of the necessary substrates are missing in the extracellular space. We also discuss the different transport mechanisms available for the entry of extracellular citrate into cancer cells and how citrate as a master metabolite enhances ATP production and fuels anabolic pathways. The available literature suggests that cancer cells show an increased metabolic flexibility with which they tackle changing environmental conditions, a phenomenon crucial for cancer cell proliferation and metastasis.
Highlights
To successfully grow and metastasise, cancer cells need to adjust their metabolism to fulfill high-energy requirements
Blocking of mCiC with BTA should decrease ROS synthesis due to the decreased mitochondrial activity rather than increase it (Fernandez et al, 2018). Most of these discrepancies could be potentially explained by our recent data showing that cancer cells of different origin can take up extracellular citrate through the plasma membrane citrate transporter pmCiC (Mycielska and Geissler, 2018; Mycielska et al, 2018, 2019), which is a variant of the mitochondrial SLC25A1. pmCiC has a different start codon which is located in the intron preceding second exon of the mCiC (Mazurek et al, 2010)
We have shown recently that cancer cells take up extracellular citrate through the pmCiC (Mycielska et al, 2015, 2018; Mycielska and Geissler, 2018), and others have shown a similar role for the Na+-coupled citrate transporter NaCT (SLC13A5) (Inoue et al, 2003; Li et al, 2017; Kopel et al, 2020)
Summary
Sebastian Haferkamp 1, Konstantin Drexler 1, Marianne Federlin 2, Hans J. Cancer cells need excess energy and essential nutrients/metabolites to divide and proliferate and to migrate and invade distant organs for metastasis. We review here potential pathways in which citrate is synthesized and/or supplied to cancer cells and the impact of extracellular citrate on cancer cell metabolism and growth. Cancer cells employ different mechanisms to support mitochondrial activity and citrate synthesis when some of the necessary substrates are missing in the extracellular space. We discuss the different transport mechanisms available for the entry of extracellular citrate into cancer cells and how citrate as a master metabolite enhances ATP production and fuels anabolic pathways. The available literature suggests that cancer cells show an increased metabolic flexibility with which they tackle changing environmental conditions, a phenomenon crucial for cancer cell proliferation and metastasis
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