Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth.
Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth.
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DOI：
10.18632/oncotarget.5843
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发表时间：
2015-12-01
期刊：
影响因子：
--
通讯作者：
Singh PK
中科院分区：
文献类型：
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作者：
Shukla SK;Dasgupta A;Mehla K;Gunda V;Vernucci E;Souchek J;Goode G;King R;Mishra A;Rai I;Nagarajan S;Chaika NV;Yu F;Singh PK
胰腺导管腺癌 (PDAC) 是美国癌症相关死亡的第四大原因。高达 80% 的 PDAC 患者存在癌症相关恶病质，并与侵袭性疾病和不良预后相关。在本研究中，我们评估了抗癌天然产物水飞蓟宾在靶向胰腺癌侵袭性以及胰腺癌细胞和肿瘤的恶病质特性方面的有效性。我们的结果表明，水飞蓟宾以剂量依赖性方式抑制胰腺癌细胞生长并降低癌细胞的糖酵解活性。我们基于 LC-MS/MS 的代谢组学数据表明，水飞蓟宾治疗可诱导胰腺癌细胞中的整体代谢重编程。水飞蓟宾治疗可减少 c-MYC 表达，c-MYC 是癌症代谢的关键调节因子。此外，我们观察到水飞蓟宾处理的癌细胞中 STAT3 信号传导减少。组成型活性 STAT3 的过度表达足以显着逆转水飞蓟宾诱导的 c-MYC 下调和代谢表型。我们的体内研究表明，水飞蓟宾可减少胰腺癌原位小鼠模型中的肿瘤生长和增殖，并防止体重和肌肉损失。它还可以改善荷瘤小鼠的身体活动，包括握力和跌倒潜伏期。总之，水飞蓟宾诱导的代谢重编程会减少胰腺癌细胞和动物模型的细胞生长和恶病质特性。
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.