Journal article
Fendiline Inhibits K-Ras Plasma Membrane Localization and Blocks K-Ras Signal Transmission
Molecular and cellular biology, Vol.33(2), pp.237-251
01/01/2013
DOI: 10.1128/MCB.00884-12
PMCID: PMC3554123
PMID: 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.
Details
- Title: Subtitle
- Fendiline Inhibits K-Ras Plasma Membrane Localization and Blocks K-Ras Signal Transmission
- Creators
- Dharini van der Hoeven - Univ Texas Houston, Sch Med, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USAKwang-jin Cho - Univ Texas Houston, Sch Med, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USAXiaoping Ma - Univ Texas Houston, Sch Med, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USASravanthi Chigurupati - Univ Texas Houston, Sch Med, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USARobert G. Parton - The University of QueenslandJohn F. Hancock - Univ Texas Houston, Sch Med, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA
- Resource Type
- Journal article
- Publication Details
- Molecular and cellular biology, Vol.33(2), pp.237-251
- DOI
- 10.1128/MCB.00884-12
- PMID
- 23129805
- PMCID
- PMC3554123
- NLM abbreviation
- Mol Cell Biol
- ISSN
- 0270-7306
- eISSN
- 1098-5549
- Publisher
- Amer Soc Microbiology
- Number of pages
- 15
- Grant note
- R90 DA023418 / Biomedical Discovery Training Program of the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (NIH) RP100483 / Cancer Prevention and Research Institute of Texas (CPRIT) R90DA023418 / NATIONAL INSTITUTE ON DRUG ABUSE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Drug Abuse (NIDA); European Commission
- Language
- English
- Date published
- 01/01/2013
- Academic Unit
- Oral Pathology, Radiology and Medicine; Dentistry Administration
- Record Identifier
- 9985157545302771
Metrics
1 Record Views