Targeting autophagic regulation of NFκB in HTLV-I transformed cells by geldanamycin -: Implications for therapeutic interventions
Targeting autophagic regulation of NFκB in HTLV-I transformed cells by geldanamycin -: Implications for therapeutic interventions
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DOI：
10.4161/auto.4761
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发表时间：
2007-11-01
期刊：
影响因子：
13.3
通讯作者：
Xiao, Gutian
中科院分区：
文献类型：
--
作者：
Yan, Pengrong;Qing, Guoliang;Xiao, Gutian
I κ B激酶（IKK）/NF κ B信号通路在多种类型癌症的发展和存活中起重要作用，包括由人T细胞白血病病毒I型（HTLV-I）感染引起的成人T细胞白血病（ATL）。因此，靶向NF κ B为癌症治疗提供了有吸引力的策略。我们最近发现格尔德霉素（geldanamycin，GA）特异性抑制热休克蛋白90（Hsp 90）可导致IKK和IKK上游激酶NF κ B诱导激酶（NIK）的自噬性降解，以及NF κ B B的失活。在此，我们进一步报道了GA抑制Hsp 90也导致IKK自噬降解和NF κ B B抑制HTLV转化的T细胞和ATL衍生的细胞系。重要的是，GA治疗导致这些恶性细胞的有效凋亡，而IKK的自噬降解的抑制显着改善GA的细胞毒性作用。因此，这些发现不仅提供了对自噬的肿瘤抑制功能和GA的抗肿瘤活性的机制性见解，而且还提出了通过靶向中心NF κ B活化激酶的自噬降解来治疗ATL和与NF κ B B活化相关的其他疾病的直接治疗策略。
The I kappa B kinase (IKK)/NF kappa B signaling pathway plays an essential role in the development and survival of many types of cancers including adult Tcell leukemia (ATL) caused by the human Tcell leukemia virus type I (HTLV-I) infection. Accordingly, targeting NF kappa B provides an attractive strategy for cancer therapy. We recently found that specific inhibition of Hsp90 by geldanamycin (GA) results in autophagic degradation of IKK and NF kappa B-inducing kinase (NIK), an upstream kinase of IKK, and inactivation of NF kappa B in various cell lines. Here, we further report that GA inhibition of Hsp90 also led to IKK autophagic degradation and NF kappa B inhibition in both HTLV-transformed T cells and ATL-derived cell lines. Importantly, GA treatment led to efficient apoptosis of these malignant cells, whereas inhibition of autophagic degradation of IKK significantly ameliorated the cytotoxic effect of GA. These findings thus not only provide mechanistic insights into the tumor suppression function of autophagy and the anti-tumor activity of GA, but also suggest an immediate therapeutic strategy for ATL and other diseases associated with NF kappa B activation by targeting autophagic degradation of the central NF kappa B activating kinases.