PGC-1α controls, to a large extent, the capacity of cells to respond to changing nutritional requirements and energetic demands. The key role of metabolic reprogramming in tumor development has highlighted the potential role of PGC-1α in cancer. To investigate how loss of PGC-1α activity in primary cells impacts the oncogenic characteristics of spontaneously immortalized cells, and the mechanisms involved, we used the classic 3T3 protocol to generate spontaneously immortalized mouse embryonic fibroblasts (iMEFs) from wild-type (WT) and PGC-1α knockout (KO) mice and analyzed their oncogenic potential in vivo and in vitro. We found that PGC-1α KO iMEFs formed larger and more proliferative primary tumors than WT counterparts, and fostered the formation of lung metastasis by B16 melanoma cells. These characteristics were associated with the reduced capacity of KO iMEFs to respond to cell contact inhibition, in addition to an increased ability to form colonies in soft agar, an enhanced migratory capacity, and a reduced growth factor dependence. The mechanistic basis of this phenotype is likely associated with the observed higher levels of nuclear β-catenin and c-myc in KO iMEFs. Evaluation of the metabolic adaptations of the immortalized cell lines identified a decrease in oxidative metabolism and an increase in glycolytic flux in KO iMEFs, which were also more dependent on glutamine for their survival. Furthermore, glucose oxidation and tricarboxylic acid cycle forward flux were reduced in KO iMEF, resulting in the induction of compensatory anaplerotic pathways. Indeed, analysis of amino acid and lipid patterns supported the efficient use of tricarboxylic acid cycle intermediates to synthesize lipids and proteins to support elevated cell growth rates. All these characteristics have been observed in aggressive tumors and support a tumor suppressor role for PGC-1α, restraining metabolic adaptations in cancer.

PGC-1α在很大程度上控制细胞响应不断变化的营养需求和能量需求的能力。代谢重编程在肿瘤发展中的关键作用凸显了 PGC-1α 在癌症中的潜在作用。为了研究原代细胞中 PGC-1α 活性的丧失如何影响自发永生化细胞的致癌特性以及所涉及的机制，我们使用经典的 3T3 协议从野生型 (WT) 和PGC-1α 敲除 (KO) 小鼠并分析其在体内和体外的致癌潜力. 我们发现 PGC-1α KO iMEFs 比 WT 对应物形成更大、更增殖的原发性肿瘤，并促进 B16 黑色素瘤细胞形成肺转移。这些特征与 KO iMEF 对细胞接触抑制的反应能力降低有关，此外，在软琼脂中形成菌落的能力增强、迁移能力增强和生长因子依赖性降低。这种表型的机制基础可能与在 KO iMEF 中观察到的较高水平的核 β-连环蛋白和 c-myc 相关。对永生化细胞系代谢适应性的评估确定了 KO iMEF 中氧化代谢的减少和糖酵解通量的增加，它们的生存也更依赖于谷氨酰胺。此外，KO iMEF 中的葡萄糖氧化和三羧酸循环正向通量减少，导致代偿性回补通路的诱导。事实上，氨基酸和脂质模式的分析支持有效使用三羧酸循环中间体来合成脂质和蛋白质以支持提高的细胞生长速率。所有这些特征已在侵袭性肿瘤中观察到，并支持 PGC-1α 的肿瘤抑制作用，抑制癌症的代谢适应。