Inhibiting 6-phosphogluconate dehydrogenase enhances chemotherapy efficacy in cervical cancer via AMPK-independent inhibition of RhoA and Rac1
Inhibiting 6-phosphogluconate dehydrogenase enhances chemotherapy efficacy in cervical cancer via AMPK-independent inhibition of RhoA and Rac1
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DOI：
10.1007/s12094-018-1937-x
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发表时间：
2019-04-01
影响因子：
3.4
通讯作者：
Sun, D.
中科院分区：
文献类型：
--
作者：
Guo, H.;Xiang, Z.;Sun, D.
背景氧化戊糖磷酸途径（PPP）对于癌症代谢和生长至关重要。然而，PPP的关键酶6-磷酸葡萄糖酸脱氢酶（6PGD）对宫颈癌发展的贡献仍然很大程度上未知。方法分析来自患者的宫颈癌细胞和组织中6PGD的mRNA和蛋白水平，并与正常细胞和组织进行比较。利用细胞培养系统和异种移植小鼠模型，确定了6PGD在宫颈癌中的功能并分析了其分子机制。使用了 6PGD 抑制剂大黄素甲醚和 siRNA 敲除。结果在这项工作中，我们证明与正常细胞相比，6PGD 在宫颈癌细胞和患者组织中异常上调和激活。使用不同的方法和临床前模型，我们发现 6PGD 抑制可减少宫颈癌的生长和迁移，并增强化疗敏感性。从机制上讲，抑制 6PGD 会激活 AMP 激活蛋白激酶 (AMPK) 并降低 RhoA 和 Rac1 活性。 AMPK 耗竭显着降低了 6PGD 抑制对降低宫颈癌细胞 RhoA 和 Rac1 活性、生长和迁移的影响。结论我们的工作首次证明了 6PGD 的异常表达及其通过 AMPK 依赖性激活在宫颈癌细胞生长和迁移中的主要作用。我们的研究结果表明 6PGD 作为增强宫颈癌化疗敏感性的潜在治疗靶点。
BackgroundThe oxidative pentose phosphate pathway (PPP) is essential for cancer metabolism and growth. However, the contribution of 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of PPP, to cervical cancer development remains largely unknown.MethodsmRNA and protein levels of 6PGD were analyzed in cervical cancer cells and tissues derived from patients and compared to normal counterparts. Using cell culture system and xenograft mouse model, the functions of 6PGD in cervical cancer are determined and its molecular mechanism is analyzed. 6PGD inhibitor physcion and siRNA knockdown were used.ResultsIn this work, we demonstrate that 6PGD is aberrantly upregulated and activated in cervical cancer cells and patient tissues compared to normal counterparts. Using different approaches and preclinical models, we show that 6PGD inhibition decreases growth and migration, and enhances chemosensitivity in cervical cancer. Mechanistically, inhibition of 6PGD activates AMP-activated protein kinase (AMPK) and decreases RhoA and Rac1 activities. AMPK depletion significantly reduces the effects of 6PGD inhibition in decreasing RhoA and Rac1 activities, growth and migration in cervical cancer cells.ConclusionsOur work is the first to demonstrate the aberrant expression of 6PGD and its predominant roles in cervical cancer cell growth and migration, via a AMPK-dependent activation. Our findings suggest 6PGD as a potential therapeutic target to enhance chemosensitivity in cervical cancer.