Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Cell. 2013 Jan 31;152(3):599-611. doi: 10.1016/j.cell.2012.12.028.
Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress. We show that PKCζ deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose. PKCζ represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity. Interestingly, the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis. Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors. Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse and human cancer.
肿瘤细胞具有高能量和合成代谢需求，已知能够适应代谢，以便在营养物质应激条件下存活并保持增殖。我们表明，PKCζ 缺乏会促进肿瘤细胞的可塑性，使它们能够通过丝氨酸生物合成途径重新编程代谢，以在没有葡萄糖的情况下利用谷氨酰胺。PKCζ 抑制该途径的两个关键酶 PHGDH 和 PSAT1 的表达，并磷酸化 PHGDH 的关键残基以抑制其酶活性。有趣的是，PKCζ 在小鼠中的缺失导致肠道肿瘤发生增强和这两种代谢酶水平升高，而 PKCζ 水平低的患者预后不良。此外，PKCζ 和 caspase-3 活性与人类肠道肿瘤中的 PHGDH 水平相关。总之，这表明 PKCζ 是小鼠和人类癌症中的关键代谢肿瘤抑制因子。
