BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton.
BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton.
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DOI：
10.1038/cddis.2014.94
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发表时间：
2014-03-13
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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BNIP 3是BCL-2蛋白家族的非典型的仅BH 3成员，其具有报道的促死亡以及促自噬和细胞保护功能，这取决于应激的类型和细胞环境。与此相一致，BNIP 3在癌症中的作用是高度有争议的，并且癌症患者中BNIP 3水平的增加与良好和不良的预后有关。在这项研究中，使用小发夹RNA（shRNA）慢病毒转导稳定敲低BNIP 3（BNIP 3-shRNA）在黑色素瘤细胞中的表达水平，我们表明BNIP 3支持癌细胞存活和长期克隆生长。尽管BNIP 3-shRNA增加了线粒体质量和活性氧产生的基线水平（这些特征与侵袭性癌细胞行为相关），但它也阻止了细胞迁移，并完全消除了在基质胶上形成管状网络的能力，这是血管生成的标志模仿（VM）。我们发现，这些黑色素瘤细胞的这种减弱的攻击性行为是通过与BNIP 3丢失相关的细胞形态学和肌动蛋白细胞骨架重塑的严重变化来强调的。事实上，BNIP 3沉默的黑色素瘤细胞表现出增强的肌动蛋白应力纤维和膜皱褶的形成，而板足突起和丝状伪足，紧密连接和粘附连接减少。此外，BNIP 3的丢失导致与磷酸化粘着斑激酶水平增加相关的粘着斑位点的重组。值得注意的是，BNIP 3沉默导致整合素相关蛋白CD 47及其下游信号效应物Rac 1和Cdc 42的蛋白水平下降。这些观察结果强调，BNIP 3需要维持细胞内复合物的稳态水平，协调肌动蛋白细胞骨架的可塑性，这是细胞迁移和刺激癌症进展的其他重要过程所不可或缺的。所有这些结果共同揭示了BNIP 3驱动黑色素瘤细胞的侵袭性特征（如迁移和VM）的前所未有的促肿瘤发生作用。
BNIP3 is an atypical BH3-only member of the BCL-2 family of proteins with reported pro-death as well as pro-autophagic and cytoprotective functions, depending on the type of stress and cellular context. In line with this, the role of BNIP3 in cancer is highly controversial and increased BNIP3 levels in cancer patients have been linked with both good as well as poor prognosis. In this study, using small hairpin RNA (shRNA) lentiviral transduction to stably knockdown BNIP3 (BNIP3-shRNA) expression levels in melanoma cells, we show that BNIP3 supports cancer cell survival and long-term clonogenic growth. Although BNIP3-shRNA increased mitochondrial mass and baseline levels of reactive oxygen species production, which are features associated with aggressive cancer cell behavior, it also prevented cell migration and completely abolished the ability to form a tubular-like network on matrigel, a hallmark of vasculogenic mimicry (VM). We found that this attenuated aggressive behavior of these melanoma cells was underscored by severe changes in cell morphology and remodeling of the actin cytoskeleton associated with loss of BNIP3. Indeed, BNIP3-silenced melanoma cells displayed enhanced formation of actin stress fibers and membrane ruffles, while lamellopodial protrusions and filopodia, tight junctions and adherens junctions were reduced. Moreover, loss of BNIP3 resulted in re-organization of focal adhesion sites associated with increased levels of phosphorylated focal adhesion kinase. Remarkably, BNIP3 silencing led to a drop of the protein levels of the integrin-associated protein CD47 and its downstream signaling effectors Rac1 and Cdc42. These observations underscore that BNIP3 is required to maintain steady-state levels of intracellular complexes orchestrating the plasticity of the actin cytoskeleton, which is integral to cell migration and other vital processes stimulating cancer progression. All together these results unveil an unprecedented pro-tumorigenic role of BNIP3 driving melanoma cell's aggressive features, like migration and VM.
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DOI：
10.1083/jcb.135.2.533
发表时间：
1996-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gao AG;Lindberg FP;Dimitry JM;Brown EJ;Frazier WA
通讯作者：
Frazier WA
影响因子：
3.7
作者：
Borm, B;Requardt, RP;Kirfel, G
通讯作者：
Kirfel, G
DOI：
10.1073/pnas.1304227110
发表时间：
2013-08-13
影响因子：
11.1
作者：
Gartner, Jared J.;Parker, Stephen C. J.;Samuels, Yardena
通讯作者：
Samuels, Yardena
影响因子：
5.3
作者：
Burton, Teralee R.;Eisenstat, David D.;Gibson, Spencer B.
通讯作者：
Gibson, Spencer B.
影响因子：
8.4
作者：
Kuphal, Silke;Winklmeier, Andreas;Bosserhoff, Anja-Katrin
通讯作者：
Bosserhoff, Anja-Katrin