Abstract
Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein acetylation. Our data suggest PCK2 promotes tumor initiation by lowering acetyl-CoA level through reducing the mitochondrial tricarboxylic acid (TCA) cycle. Thus, PCK2 is a potential therapeutic target for aggressive prostate tumors.
Highlights
Emerging data suggest that a subpopulation of self-renewing and evolving tumor-initiating cells (TICs), popularly known as cancer stem cells (CSCs), may be responsible for tumor metastasis, and patient relapse and death [1]
Www.impactjournals.com/oncotarget first round),13C3-citrate and 13C4 (M4)-citrate (Figures 4F, 4G, 4H, and 4I). These results further indicated that phosphoenolpyruvate carboxykinase isoform 2 (PCK2) can remodel the glucose metabolism in Tumor-initiating cells (TICs)-enriched prostate cancer cells, by enhancing glycolysis and reducing the tricarboxylic acid (TCA) cycle
We grew up subclones from single cells of heterogeneous prostate cancer cell lines to obtain TICenriched and TIC-impoverished clones
Summary
Emerging data suggest that a subpopulation of self-renewing and evolving tumor-initiating cells (TICs), popularly known as cancer stem cells (CSCs), may be responsible for tumor metastasis, and patient relapse and death [1]. TICs are resistant to both radiation and chemotherapy in conventional treatments [3, 4]. Such treatments enrich TICs in tumors, endowing them with more aggressive characteristics. More than 75 years ago, Otto Warburg observed that tumor cells, like embryonic cells, preferentially use glycolysis to convert glucose carbon to lactate, even under aerobic conditions [5]. Reports have shown that a single switch to the embryonic isoform of pyruvate kinase (PKM2) is necessary for the shift from OXPHOS to glycolysis in cancer cells and that this switch promotes tumorigenesis [6, 7]. The enhanced glycolysis in cancer cells can decrease reactive oxygen species (ROS), and promote the pentose phosphate pathway (PPP) and serine/glycine synthesis pathway, which are both linked to tumorigenesis [8,9,10,11]
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