Oncogene：细胞死亡之谜为开发癌症药物带来新思路

近日，北卡罗莱纳大学教堂山分校生物化学系教授Leslie Parise博士在实验室中发现的一种蛋白质CIB1。这一小的钙结合蛋白被发现在所有类型细胞中都存在。Cassandra Moran是UNC儿科肿瘤学研究员，她的研究领域是神经母细胞瘤。Cassandra Moran发现，在神经母细胞瘤细胞中降低CIB1，会导致细胞死亡。癌症是因为细胞生长失控所导致的疾病，因此研究人员在实验室所发现的CIB1缺失导致肿瘤细胞死亡是非常令人兴奋的研究结果，但UNC研究人员目前还无法弄清楚其中机制。

CIB1缺失造成细胞死亡是一个谜。正常细胞半胱天冬酶被激活后，细胞DNA遭到破坏，导致出现程序性细胞死亡即细胞凋亡。但这些神经母细胞瘤细胞的半胱天冬酶并不处于激活状态，但这些细胞确实发生了死亡现象。

Leisner博士说：这项研究结果即使令人惊喜的，但同时又令人感到沮丧。研究发现CIB1是癌细胞避免正常程序性细胞死亡的两种信号途径的主要控调节因子。研究人员认为，这两条信号途径可以帮助肿瘤细胞逃避药物治疗，并且继续存活和增殖。

当一条途径被阻断后，另一条信号仍然能给下游发送信号造成肿瘤细胞的生存。研究人员最终发现是，CIB1处于这两个细胞存活信号途径的核心调控部位，也即调控PI3K/Akt和MEK / ERK通路，当研究人员抑制CIB1后，这两条信号途径将不发挥作用，肿瘤细胞就会出现死亡。

细胞缺失AKT信号，造成另一种酶GAPDH在细胞核中积累。而细胞缺失ERK信号后GAPDH也在细胞核中积累，最终导致神经母细胞瘤细胞死亡。生物化学研究人员Parise博士表示阻断CIB1调控细胞生长不受控制的信号通路或许是一个非常有前途的药物靶标。

doi:10.1038/onc.2012.408
PMC:
PMID:

CIB1 prevents nuclear GAPDH accumulation and non-apoptotic tumor cell death via AKT and ERK signaling

T M Leisner, C Moran, S P Holly and L V Parise

CIB1 is a 22-kDa regulatory protein previously implicated in cell survival and proliferation. However, the mechanism by which CIB1 regulates these processes is poorly defined. Here, we report that CIB1 depletion in SK-N-SH neuroblastoma and MDA-MB-468 breast cancer cells promotes non-apoptotic, caspase-independent cell death that is not initiated by increased outer mitochondrial membrane permeability or translocation of apoptosis-inducing factor to the nucleus. Instead, cell death requires nuclear GAPDH accumulation. Furthermore, CIB1 depletion disrupts two commonly dysregulated, oncogenic pathways—PI3K/AKT and Ras/MEK/ERK, resulting in a synergistic mechanism of cell death, which was mimicked by simultaneous pharmacological inhibition of both pathways, but not either pathway alone. In defining each pathway’s contributions, we found that AKT inhibition alone maximally induced GAPDH nuclear accumulation, whereas MEK/ERK inhibition alone had no effect on GAPDH localization. Concurrent GAPDH nuclear accumulation and ERK inhibition were required, however, to induce a significant DNA damage response, which was critical to subsequent cell death. Collectively, our results indicate that CIB1 is uniquely positioned to regulate PI3K/AKT and MEK/ERK signaling and that simultaneous disruption of these pathways synergistically induces a nuclear GAPDH-dependent cell death. The mechanistic insights into cell death induced by CIB1 interference suggest novel molecular targets for cancer therapy.