Carragher N O, Fonseca B D, Frame M C
The Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Glasgow G61 1BD, Scotland, UK.
Neoplasia. 2004 Jan-Feb;6(1):53-73. doi: 10.1016/s1476-5586(04)80053-8.
Several oncogene and tumor-suppressor gene products are known substrates for the calpain family of cysteine proteases, and calpain is required for transformation by v-src and tumor invasion. Thus, we have now addressed whether calpain is generally associated with transformation and how calpain contributes to oncogene function. Our results demonstrate that calpain activity is enhanced upon transformation induced by the v-Src, v-Jun, v-Myc, k-Ras, and v-Fos oncoproteins. Furthermore, elevated calpain activity commonly promotes focal adhesion remodelling, disruption of actin cytoskeleton, morphological transformation, and cell migration, although proteolysis of target substrates (such as focal adhesion kinase, talin, and spectrin) is differently specified by individual oncoproteins. Interestingly, v-Fos differs from other common oncoproteins in not requiring calpain activity for actin/adhesion remodelling or migration of v-Fos transformed cells. However, anchorage-independent growth of all transformed cells is sensitive to calpain inhibition. In addition, elevated calpain activity contributes to oncogene-induced apoptosis associated with transformation by v-Myc. Taken together, these studies demonstrate that calpain activity is necessary for full cellular transformation induced by common oncoproteins, but has distinct roles in oncogenic events induced by individual transforming proteins. Thus, targeting calpain activity may represent a useful general strategy for interfering with activated proto-oncogenes in cancer cells.
已知几种癌基因和肿瘤抑制基因产物是半胱氨酸蛋白酶钙蛋白酶家族的底物，并且v-src诱导的转化和肿瘤侵袭需要钙蛋白酶。因此，我们现在研究了钙蛋白酶是否通常与转化相关，以及钙蛋白酶如何促进癌基因功能。我们的结果表明，在v-Src、v-Jun、v-Myc、k-Ras和v-Fos癌蛋白诱导的转化过程中，钙蛋白酶活性增强。此外，钙蛋白酶活性升高通常会促进粘着斑重塑、肌动蛋白细胞骨架破坏、形态转化和细胞迁移，尽管单个癌蛋白对靶底物（如粘着斑激酶、踝蛋白和血影蛋白）的蛋白水解作用有所不同。有趣的是，v-Fos与其他常见癌蛋白不同，v-Fos转化细胞的肌动蛋白/粘着重塑或迁移不需要钙蛋白酶活性。然而，所有转化细胞的非锚定依赖性生长对钙蛋白酶抑制敏感。此外，钙蛋白酶活性升高导致v-Myc诱导的与转化相关的细胞凋亡。综上所述，这些研究表明，钙蛋白酶活性是常见癌蛋白诱导完全细胞转化所必需的，但在单个转化蛋白诱导的致癌事件中具有不同作用。因此，靶向钙蛋白酶活性可能是干扰癌细胞中活化原癌基因的一种有用的通用策略。
