Fendiline inhibits K-Ras plasma membrane localization and blocks K-Ras signal transmission.
Mol Cell Biol
; 33(2): 237-51, 2013 Jan.
Article
en En
| MEDLINE
| ID: mdl-23129805
ABSTRACT
Ras proteins regulate signaling pathways important for cell growth, differentiation, and survival. Oncogenic mutant Ras proteins are commonly expressed in human tumors, with mutations of the K-Ras isoform being most prevalent. To be active, K-Ras must undergo posttranslational processing and associate with the plasma membrane. We therefore devised a high-content screening assay to search for inhibitors of K-Ras plasma membrane association. Using this assay, we identified fendiline, an L-type calcium channel blocker, as a specific inhibitor of K-Ras plasma membrane targeting with no detectable effect on the localization of H- and N-Ras. Other classes of L-type calcium channel blockers did not mislocalize K-Ras, suggesting a mechanism that is unrelated to calcium channel blockade. Fendiline did not inhibit K-Ras posttranslational processing but significantly reduced nanoclustering of K-Ras and redistributed K-Ras from the plasma membrane to the endoplasmic reticulum (ER), Golgi apparatus, endosomes, and cytosol. Fendiline significantly inhibited signaling downstream of constitutively active K-Ras and endogenous K-Ras signaling in cells transformed by oncogenic H-Ras. Consistent with these effects, fendiline blocked the proliferation of pancreatic, colon, lung, and endometrial cancer cell lines expressing oncogenic mutant K-Ras. Taken together, these results suggest that inhibitors of K-Ras plasma membrane localization may have utility as novel K-Ras-specific anticancer therapeutics.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Bloqueadores de los Canales de Calcio
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Fendilina
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Transducción de Señal
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Membrana Celular
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Proteínas Proto-Oncogénicas
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Proteínas ras
Límite:
Animals
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Humans
Idioma:
En
Revista:
Mol Cell Biol
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos