Inhibition of GSK-3 induces differentiation and impaired glucose metabolism in renal cancer.
Inhibition of GSK-3 induces differentiation and impaired glucose metabolism in renal cancer.
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DOI：
10.1158/1535-7163.mct-13-0681
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发表时间：
2014-02
影响因子：
5.7
通讯作者：
Mukhopadhyay D
中科院分区：
文献类型：
--
作者：
Pal K;Cao Y;Gaisina IN;Bhattacharya S;Dutta SK;Wang E;Gunosewoyo H;Kozikowski AP;Billadeau DD;Mukhopadhyay D
糖原合成酶激酶-3 （GSK-3）是一种组成活性的丝氨酸/苏氨酸激酶，是许多细胞过程的关键调节剂，从糖原代谢到细胞周期调节和增殖。与其参与许多途径一致，它也涉及各种人类疾病的发病机制，包括II型糖尿病、阿尔茨海默病、双相情感障碍、炎症和癌症。因此，它被认为是开发新药的一个有吸引力的目标。在本研究中，我们研究了GSK-3在两种不同的肾癌细胞系中的药理和遗传抑制作用。我们已经证明了基于马来酰亚胺的GSK-3抑制剂9-ING-41具有有效的抗增殖活性。从细胞周期分析可以看出，抗增殖活性很可能是由G0-G1和G2-M期阻滞引起的。我们已经确定GSK-3的抑制使肾癌细胞的表型分化。我们还表明GSK-3抑制诱导自噬，可能是由于葡萄糖代谢受损引起的能量稳态不平衡。此外，我们已经在两种不同的皮下异种移植RCC肿瘤模型中证明了9-ING-41的抗肿瘤活性。据我们所知，这是第一个描述肾癌细胞中GSK-3抑制诱导自噬的报道。
Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, is a key regulator of numerous cellular processes ranging from glycogen metabolism to cell cycle regulation and proliferation. Consistent with its involvement in many pathways, it has also been implicated in the pathogenesis of various human diseases including Type II diabetes, Alzheimer's disease, bipolar disorder, inflammation and cancer. Consequently it is recognized as an attractive target for the development of new drugs. In the present study, we investigated the effect of both pharmacological and genetic inhibition of GSK-3 in two different renal cancer cell lines. We have shown potent anti-proliferative activity of 9-ING-41, a maleimide-based GSK-3 inhibitor. The anti-proliferative activity is most likely caused by G0–G1 and G2-M phase arrest as evident from cell cycle analysis. We have established that inhibition of GSK-3 imparted a differentiated phenotype in renal cancer cells. We have also shown that GSK-3 inhibition induced autophagy, likely as a result of imbalanced energy homeostasis caused by impaired glucose metabolism. Additionally, we have demonstrated the antitumor activity of 9-ING-41 in two different subcutaneous xenograft RCC tumor models. To our knowledge, this is the first report describing autophagy induction due to GSK-3 inhibition in renal cancer cells.