1Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, CA USA.
2Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Signal Transduct Target Ther. 2019 Jan 25;4:2. doi: 10.1038/s41392-019-0035-z. eCollection 2019.
Renal cell carcinoma (RCC) has emerged as a metabolic disease characterized by dysregulated expression of metabolic enzymes. Patients with metastatic RCC have an unusually poor prognosis and near-universal resistance to all current therapies. To improve RCC treatment and the survival rate of patients with RCC, there is an urgent need to reveal the mechanisms by which metabolic reprogramming regulates aberrant signaling and oncogenic progression. Through an integrated analysis of RCC metabolic pathways, we showed that methylthioadenosine phosphorylase (MTAP) and its substrate methylthioadenosine (MTA) are dysregulated in aggressive RCC. A decrease in MTAP expression was observed in RCC tissues and correlated with higher tumor grade and shorter overall survival. Genetic manipulation of MTAP demonstrated that MTAP expression inhibits the epithelial-mesenchymal transition, invasion and migration of RCC cells. Interestingly, we found a decrease in the protein methylation level with a concomitant increase in tyrosine phosphorylation after MTAP knockout. A phospho-kinase array screen identified the type 1 insulin-like growth factor-1 receptor (IGF1R) as the candidate with the highest upregulation in tyrosine phosphorylation in response to MTAP loss. We further demonstrated that IGF1R phosphorylation acts upstream of Src and STAT3 signaling in MTAP-knockout RCC cells. IGF1R suppression by a selective inhibitor of IGF1R, linsitinib, impaired the cell migration and invasion capability of MTAP-deleted cells. Surprisingly, an increase in linsitinib-mediated cytotoxicity occurred in RCC cells with MTAP deficiency. Our data suggest that IGF1R signaling is a driver pathway that contributes to the aggressive nature of MTAP-deleted RCC.
肾细胞癌 (RCC) 已成为一种代谢疾病，其特征是代谢酶表达失调。转移性 RCC 患者的预后异常差，几乎对所有现有治疗方法均具有耐药性。为了改善 RCC 的治疗效果和提高 RCC 患者的生存率，迫切需要揭示代谢重编程调节异常信号和致癌进展的机制。通过对 RCC 代谢途径的综合分析，我们表明甲基硫腺苷磷酸化酶 (MTAP) 及其底物甲基硫腺苷 (MTA) 在侵袭性 RCC 中失调。在 RCC 组织中观察到 MTAP 表达减少，且与更高的肿瘤分级和更短的总生存期相关。MTAP 的遗传操作表明 MTAP 表达抑制了 RCC 细胞的上皮-间充质转化、侵袭和迁移。有趣的是，我们发现 MTAP 敲除后，蛋白质甲基化水平降低，酪氨酸磷酸化增加。磷酸激酶阵列筛选确定 1 型胰岛素样生长因子-1 受体 (IGF1R) 是酪氨酸磷酸化反应中上调最高的候选物。我们进一步证明，在 MTAP 敲除的 RCC 细胞中，IGF1R 磷酸化作用于 Src 和 STAT3 信号的上游。通过 IGF1R 的选择性抑制剂 linsitinib 抑制 IGF1R，可损害 MTAP 缺失细胞的迁移和侵袭能力。令人惊讶的是，在 MTAP 缺陷的 RCC 细胞中，增加 linsitinib 介导的细胞毒性作用。我们的数据表明，IGF1R 信号是驱动 MTAP 缺失的 RCC 侵袭性的途径。
