TCA cycle nutrient use and invasiveness of ovarian cancer

Schematic showing the shift in nutrient utilization in TCA cycle with increasing degree of invasiveness. Low-invasive ovarian cancer (OVCA) cells are glucose dependent for their TCA cycle pool. With increasing invasiveness in cancer cells, dominant nutrient which feeds the TCA cycle shifts from glucose to Gln. In high-invasive OVCA cells, Gln dominates the TCA cycle. In low-invasive OVCA cells, glucose activates Jak1, which activates STAT3 by tyrosine phosphorylation, thereby regulating glycolysis in cancer cells. In highinvasive OVCA cells, besides glucose's role in activating STAT3 tyrosine phosphorylation, glutamine activates JAK1 through TCA cycle to further activate STAT3 by tyrosine phosphorylation and thus regulate glycolysis. Further, Gln activates Erk1/2, which subsequently activates STAT3 by serine phosphorylation selectively in high-invasive OVCA cells. The serine phosphorylation of STAT3 enhances oxidative phosphorylation in mitochondria by interaction with mitochondrial complexes I and II, thereby increasing TCA cycle activity in high-invasive OVCA cells.

图示随着肿瘤细胞侵袭程度的增加，三羧酸循环中营养利用的转变。低侵袭性卵巢癌（OVCA）细胞依赖于葡萄糖为其三羧酸循环库提供能量。随着肿瘤细胞的侵袭程度增强，为三羧酸循环提供能量的主要营养素从葡萄糖转变为谷氨酰胺。在高侵袭性OVCA细胞中，谷氨酰胺主导三羧酸循环。在低侵袭性OVCA细胞中，葡萄糖通过激活Jak1，进而通过酪氨酸磷酸化激活STAT3，从而调节肿瘤细胞的糖酵解。在高侵袭性OVCA细胞中，除了葡萄糖在激活STAT3酪氨酸磷酸化中的作用外，谷氨酰胺通过三羧酸循环激活JAK1，进一步通过酪氨酸磷酸化激活STAT3，从而调节糖酵解。此外，谷氨酰胺激活Erk1/2，随后在高度侵袭性OVCA细胞中通过丝氨酸磷酸化选择性地激活STAT3。STAT3的丝氨酸磷酸化通过与线粒体复合物I和II相互作用，增强线粒体的氧化磷酸化，从而提高高侵袭性OVCA细胞中三羧酸循环的活性。