Shait Mohammed Mohammed Razeeth, Alghamdi Raed Ahmed, Alzahrani Abdulaziz Musa, Zamzami Mazin A, Choudhry Hani, Khan Mohammad Imran
Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
Cancer Metabolism and Epigenetic Unit, Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
Front Oncol. 2021 Feb 25;11:612778. doi: 10.3389/fonc.2021.612778. eCollection 2021.
Most of the cancer related deaths are caused mainly by metastasis. Therefore, it is highly important to unfold the major mechanisms governing metastasis process in cancer. Throughout the metastatic cascade, cells need the ability to survive without attachment to neighboring cells and the original Extra Cellular Matrix (ECM). Recent reports showed that loss of ECM attachment shifts cancer cell metabolism towards glycolysis mostly through hypoxia. However, AMPK, a master metabolic regulator was also found to be upregulated under ECM detached conditions. Therefore, in this work we aimed to understand the consequences of targeting AMPK and other metabolic kinases by a broad kinase inhibitor namely Compound C in ECM detached cancer cells. Results showed that Compound C impacts glycolysis as evident by increased levels of pyruvate, but reduces its conversion to lactate thereby negatively regulating the Warburg effect. Simultaneously, Compound C induces block at multiple levels in TCA cycle as evident from accumulation of various TCA metabolites. Interestingly Compound C significantly reduces glutamine and reduced glutathione levels, suggesting loss of antioxidant potential of ECM detached cancer cells. Further, we found increased in metabolites associated with nucleotide synthesis, one carbon metabolism and PPP pathway during Compound C treatment of ECM detached cells. Finally, we also found induction in metabolites associated with DNA damage in ECM detached cancer cells during Compound C treatment, suggesting DNA damage regulatory role of metabolic kinases. Overall, our results showed that Compound C represses pyruvate to lactate conversion, reduces antioxidant potential and invokes DNA damage in ECM detached cancer cells. Our data provides a comprehensive metabolic map of ECM detached cancer cells that can be targeted with a broad kinase inhibitor, is Compound C. The data can be used for designing new combinational therapies to eradicate ECM detached cancer cells.
大多数癌症相关死亡主要是由转移引起的。因此，揭示癌症转移过程的主要机制非常重要。在整个转移级联过程中，细胞需要在不附着于邻近细胞和原始细胞外基质（ECM）的情况下存活的能力。最近的报告表明，ECM附着的丧失主要通过缺氧使癌细胞代谢转向糖酵解。然而，人们还发现，作为主要代谢调节因子的AMPK在ECM脱离条件下也会上调。因此，在这项研究中，我们旨在了解一种广泛的激酶抑制剂即化合物C靶向AMPK和其他代谢激酶对ECM脱离的癌细胞的影响。结果表明，化合物C对糖酵解有影响，丙酮酸水平升高就证明了这一点，但它会减少丙酮酸向乳酸的转化，从而对瓦伯格效应产生负调控。同时，化合物C在三羧酸循环的多个水平上诱导阻滞，各种三羧酸代谢物的积累就证明了这一点。有趣的是，化合物C显著降低了谷氨酰胺和还原型谷胱甘肽水平，这表明ECM脱离的癌细胞抗氧化能力丧失。此外，我们发现在用化合物C处理ECM脱离的细胞过程中，与核苷酸合成、一碳代谢和磷酸戊糖途径相关的代谢物增加。最后，我们还发现在用化合物C处理ECM脱离的癌细胞过程中，与DNA损伤相关的代谢物增加，这表明代谢激酶具有DNA损伤调节作用。总体而言，我们的结果表明，化合物C抑制丙酮酸向乳酸的转化，降低抗氧化能力，并在ECM脱离的癌细胞中引发DNA损伤。我们的数据提供了ECM脱离的癌细胞的全面代谢图谱，一种广泛的激酶抑制剂即化合物C可以靶向该图谱。这些数据可用于设计新的联合疗法以根除ECM脱离的癌细胞。
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