Simultaneous inhibition of mTOR-containing complex 1 (mTORC1) and MNK induces apoptosis of cutaneous T-cell lymphoma (CTCL) cells.
Simultaneous inhibition of mTOR-containing complex 1 (mTORC1) and MNK induces apoptosis of cutaneous T-cell lymphoma (CTCL) cells.
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DOI：
10.1371/journal.pone.0024849
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wasik MA
中科院分区：
文献类型：
--
作者：
Marzec M;Liu X;Wysocka M;Rook AH;Odum N;Wasik MA
mTOR激酶通过与raptor和其他蛋白结合形成mTORC1复合物，并影响许多关键的细胞功能。mTORC1激活p70S6kinase 1 (p70S6K1)，抑制4e结合蛋白1 （4E-BP1）。反过来，p70S6K1磷酸化40S核糖体亚基（S6rp）和4E- bp1的S6蛋白，后者负调控真核起始因子4E （eIF-4E）。MNK1和MNK2激酶磷酸化并增强eIF4E的活性。雷帕霉素及其类似物是高度特异、有效且相对无毒的mTORC1抑制剂。尽管mTORC1激活存在于许多类型的恶性肿瘤中，但雷帕霉素型抑制剂作为单一药物的临床疗效相对有限。最初通常是无痛的，CTCL表现出向侵袭性形式发展的趋势，对治疗的反应有限，预后差。我们之前的研究（M. Marzec et al. 2008）表明CTCL细胞显示mTORC1激活，用雷帕霉素短期治疗CTCL来源的细胞抑制了它们的增殖，对细胞存活几乎没有影响。用mTORC1抑制剂雷帕霉素和MNK抑制剂处理CTCL细胞，并评估mTORC1信号通路和细胞生长和存活的抑制作用。而雷帕霉素持续抑制mTORC1信号传导，它只抑制部分细胞生长。MNK激酶介导eIF4E磷酸化，当MNK的抑制或耗尽与雷帕霉素介导的mTORC1抑制联合使用时，可显著抑制CTCL细胞的增殖。MNK单独抑制可轻度抑制CTCL细胞的生长，而MNK和mTORC1联合抑制可完全抑制CTCL细胞的生长。同样，单独使用MNK抑制剂也显示出最小的促凋亡作用；与雷帕霉素联用可引起细胞深度凋亡。这些发现表明mTORC1和MNK的联合抑制可能对CTCL和其他恶性肿瘤的治疗有益。
mTOR kinase forms the mTORC1 complex by associating with raptor and other proteins and affects a number of key cell functions. mTORC1 activates p70S6kinase 1 (p70S6K1) and inhibits 4E-binding protein 1 (4E-BP1). In turn, p70S6K1 phosphorylates a S6 protein of the 40S ribosomal subunit (S6rp) and 4E-BP1, with the latter negatively regulating eukaryotic initiation factor 4E (eIF-4E). MNK1 and MNK2 kinases phosphorylate and augment activity of eIF4E. Rapamycin and its analogs are highly specific, potent, and relatively non-toxic inhibitors of mTORC1. Although mTORC1 activation is present in many types of malignancies, rapamycin-type inhibitors shows relatively limited clinical efficacy as single agents. Initially usually indolent, CTCL displays a tendency to progress to the aggressive forms with limited response to therapy and poor prognosis. Our previous study (M. Marzec et al. 2008) has demonstrated that CTCL cells display mTORC1 activation and short-term treatment of CTCL-derived cells with rapamycin suppressed their proliferation and had little effect on the cell survival. Cells derived from CTCL were treated with mTORC1 inhibitor rapamycin and MNK inhibitor and evaluated for inhibition of the mTORC1 signaling pathway and cell growth and survival. Whereas the treatment with rapamycin persistently inhibited mTORC1 signaling, it suppressed only partially the cell growth. MNK kinase mediated the eIF4E phosphorylation and inhibition or depletion of MNK markedly suppressed proliferation of the CTCL cells when combined with the rapamycin-mediated inhibition of mTORC1. While MNK inhibition alone mildly suppressed the CTCL cell growth, the combined MNK and mTORC1 inhibition totally abrogated the growth. Similarly, MNK inhibitor alone displayed a minimal pro-apoptotic effect; in combination with rapamycin it triggered profound cell apoptosis. These findings indicate that the combined inhibition of mTORC1 and MNK may prove beneficial in the treatment of CTCL and other malignancies.
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