Deciphering the signaling networks underlying simvastatin-induced apoptosis in human cancer cells: evidence for non-canonical activation of RhoA and Rac1 GTPases

PDF Version Also Available for Download.

Description

Article on deciphering the signaling networks underlying simvastatin-induced apoptosis in human cancer cells and evidence for non-canonical activation of RhoA and Rac1 GTPases.

Physical Description

12 p.

Creation Information

Zhu, Y.; Casey, Patrick J.; Kumar, Alan Prem & Pervaiz, Shazib 2013.

Context

This article is part of the collection entitled: UNT Scholarly Works and was provided by UNT College of Arts and Sciences to Digital Library, a digital repository hosted by the UNT Libraries. It has been viewed 129 times . More information about this article can be viewed below.

Who

People and organizations associated with either the creation of this article or its content.

Authors

  • Zhu, Y. National University of Singapore
  • Casey, Patrick J. Duke University Medical Center; Duke-NUS Graduate Medical School, Singapore
  • Kumar, Alan Prem University of North Texas; Yong Loo Lin School of Medicine; Cancer Science Institute of Singapore; Curtin University
  • Pervaiz, Shazib University of North Texas; National University of Singapore; Duke-NUS Graduate Medical School, Singapore; Singapore-MIT Alliance

Publisher

Provided By

UNT College of Arts and Sciences

The UNT College of Arts and Sciences educates students in traditional liberal arts, performing arts, sciences, professional, and technical academic programs. In addition to its departments, the college includes academic centers, institutes, programs, and offices providing diverse courses of study.

Contact Us

What

Descriptive information to help identify this article. Follow the links below to find similar items on the Digital Library.

Degree Information

Description

Article on deciphering the signaling networks underlying simvastatin-induced apoptosis in human cancer cells and evidence for non-canonical activation of RhoA and Rac1 GTPases.

Physical Description

12 p.

Notes

Abstract: Although statins are known to inhibit proliferation and induce death in a number of cancer cell types, the mechanisms through which downregulation of the mevalonate (MVA) pathway activates death signaling remain poorly understood. Here we set out to unravel the signaling networks downstream of the MVA pathway that mediate the death-inducing activity of simvastatin. Consistent with previous reports, exogenously added geranylgeranylpyrophosphate, but not farnesylpyrophosphate, prevented simvastatin's growth-inhibitory effect, thereby suggesting the involvement of geranylgeranylated proteins such as Rho GTPases in the anticancer activity of simvastatin. Indeed, simvastatin treatment led to increased levels of unprenylated Ras homolog gene family, member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42). Intriguingly, instead of inhibiting the functions of Rho GTPases as was expected with loss of prenylation, simvastatin caused a paradoxical increase in the GTP-bound forms in RhoA, Rac1 and Cdc42. Furthermore, simvastatin disrupted the binding of Rho GTPases with the cytosolic inhibitor Rho GDIx, which provides a potential mechanism for GTP loading of the cytostolic Rho GTPases. We also show that the unprenylated RhoA- and Rac1-GTP retained at least part of their functional activities, as evidenced by the increase in intracellular superoxide production and JNK activation in response to simvastatin. Notably, blocking superoxide production attenuated JNK activation as well as cell death induced by simvastatin. Finally, we provide evidence for the involvement of the B-cell lymphoma protein 2 family, Bcl-2-interacting mediator (Bim), in a JNK-dependent manner, in the apoptosis-inducing activity of simvastatin. Taken together, our data highlight the critical role of non-canonical regulation of Rho GTPases and involvement of downstream superoxide-mediated activation of JNK pathway in the anticancer activity of simvastatin, which would have potential clinical implications.

Copyright © 2013 Nature Publishing Group.

Subjects

Source

  • Cell Death and Disease, 2013, London: Nature Publishing Group

Language

Item Type

Identifier

Unique identifying numbers for this article in the Digital Library or other systems.

Publication Information

  • Publication Title: Cell Death and Disease
  • Pages: 12
  • Peer Reviewed: Yes

Collections

This article is part of the following collection of related materials.

UNT Scholarly Works

Materials from the UNT community's research, creative, and scholarly activities and UNT's Open Access Repository. Access to some items in this collection may be restricted.

What responsibilities do I have when using this article?

When

Dates and time periods associated with this article.

Creation Date

  • 2013

Added to The UNT Digital Library

  • May 7, 2014, 12:22 a.m.

Usage Statistics

When was this article last used?

Yesterday: 0
Past 30 days: 2
Total Uses: 129

Interact With This Article

Here are some suggestions for what to do next.

Start Reading

PDF Version Also Available for Download.

International Image Interoperability Framework

IIF Logo

We support the IIIF Presentation API

Zhu, Y.; Casey, Patrick J.; Kumar, Alan Prem & Pervaiz, Shazib. Deciphering the signaling networks underlying simvastatin-induced apoptosis in human cancer cells: evidence for non-canonical activation of RhoA and Rac1 GTPases, article, 2013; [London, United Kingdom]. (digital.library.unt.edu/ark:/67531/metadc284570/: accessed September 21, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.