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细胞极性蛋白质在应对代谢压力的过程中促进巨型皮诺细胞形成

Guillem Lambies¹, Szu-Wei Lee¹, Karen Duong-Polk¹

¹Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Nature communications

|December 3, 2024

概括

非典型蛋白激酶C (aPKC) 酶调节巨细胞酶,这是一个营养清理途径,对癌细胞存活至关重要. 这些aPKC对胰腺管腺癌 (PDAC) 的生长至关重要,提供潜在的治疗点.

科学领域:

细胞生物学细胞生物学
癌症生物学癌症生物学
分子瘤学分子瘤学

背景情况:

巨细胞瘤是一种细胞吸收机制,被癌细胞利用,特别是胰腺管道腺癌 (PDAC),以在营养不良的条件下生存.
谷氨胺缺乏会增强PDAC细胞中的巨型皮诺细胞形成,突显了营养可用性在癌症生存策略中的作用.

研究的目的:

在代谢应激的背景下,确定宏皮诺细胞形成的关键调节者.
阐明通过非典型蛋白激酶C (aPKC) 酶控制巨细胞瘤的分子机制.

主要方法:

研究了非典型蛋白质激酶C (aPKC) 酶,特别是PKCζ和PKCι在调节巨细胞结核中的作用.
研究了aPKC与Par3和Par6支架蛋白的关联及其对细胞极性的影响.
研究了EGFR信号和CREM对aPKCs的调节,以及它们对Par3转移到微管细胞的影响.

主要成果:

确定了aPKC酶 (PKCζ和PKCι) 作为巨细胞瘤的关键调节剂.
证明aPKCs与Par3和Par6一起,是宏皮诺细胞形成的必要条件.
表明aPKCs以dynein依赖的方式促进Par3转移到微管中,从而促进巨细胞.
发现aPKC的枯竭会损害细胞的健康状况,可以通过恢复巨型皮诺细胞形成来挽救.
在体内证实aPKCs支持PDAC瘤生长.

结论:

aPKC酶是巨细胞细胞分裂的关键媒介,在代谢压力下对癌细胞生存至关重要.
aPKC-Par3-Par6复合体在通过细胞骨动力学调节巨细胞形成中起着至关重要的作用.
针对aPKCs可能是一个可行的策略,通过破坏必需营养物质清理途径来抑制PDAC生长.

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