Zhou Ying, Uddin Shahab, Zimmerman Todd, Kang Jeong-Ah, Ulaszek Jodie, Wickrema Amittha
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Leuk Lymphoma. 2008 Oct;49(10):1945-53. doi: 10.1080/10428190802304966.
Anti-apoptotic pathways play a central role in the survival of multiple myeloma cells. The contribution of PI3-kinase and Akt kinase in mediating myeloma cell survival is well established although the role of glycogen synthase kinase-3 (GSK3) is less defined. In this study we determined the contribution of GSK3 in growth regulation of myeloma cells. We treated six different multiple myeloma cell lines with a Thiadiazolidinone (TDZD), a non-competitive inhibitor of GSK3 and determined its effects on proliferation and apoptosis. In addition we determined the activation of forkhead transcription factors (FOXO) in response to TDZD. TDZD inhibited proliferation and induced apoptosis of all myeloma cell lines. TDZD was also effective in inducing apoptosis of primary myeloma cells whereas CD34 positive normal hematopoietic cells were protected from apoptosis. Furthermore, TDZD-mediated inhibition of GSK3 resulted in dephosphorylation and activation of FOXO3a. In primary myeloma cells FOXO transcription factors were highly phosphorylated where as the levels of GSK3 phosphorylation was quite low. The levels of the pro-apoptotic proteins Fas ligand (FasL) and IkappaBalpha increased after treatment with TDZD in myeloma cell lines. These studies provide the basis for further testing of GSK3 inhibitors in the clinical setting.
抗凋亡通路在多发性骨髓瘤细胞的存活中起着核心作用。尽管糖原合酶激酶-3（GSK3）的作用尚不太明确，但PI3激酶和Akt激酶在介导骨髓瘤细胞存活中的作用已得到充分证实。在本研究中，我们确定了GSK3在骨髓瘤细胞生长调控中的作用。我们用噻二唑烷酮（TDZD）（一种GSK3的非竞争性抑制剂）处理六种不同的多发性骨髓瘤细胞系，并确定其对增殖和凋亡的影响。此外，我们还确定了叉头转录因子（FOXO）对TDZD的反应激活情况。TDZD抑制了所有骨髓瘤细胞系的增殖并诱导了凋亡。TDZD在诱导原发性骨髓瘤细胞凋亡方面也很有效，而CD34阳性正常造血细胞则免受凋亡影响。此外，TDZD介导的GSK3抑制导致FOXO3a的去磷酸化和激活。在原发性骨髓瘤细胞中，FOXO转录因子高度磷酸化，而GSK3的磷酸化水平相当低。用TDZD处理骨髓瘤细胞系后，促凋亡蛋白Fas配体（FasL）和IkappaBalpha的水平升高。这些研究为在临床环境中进一步测试GSK3抑制剂提供了依据。
