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Differential interference of chlorpromazine with the membrane interactions of oncogenic K-Ras and its effects on cell

Sharon Eisenberg1, Klaudia Giehl, Yoav I Henis

  • 1Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.

The Journal of Biological Chemistry
|August 12, 2008
PubMed

Insights

The drug chlorpromazine (CPZ) disrupts the membrane attachment of oncogenic K-Ras proteins, leading to cell cycle arrest or apoptosis. This disruption affects cancer cell phenotypes like migration and growth.

Area of Science:

  • Molecular and Cellular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Membrane anchorage is crucial for Ras protein signaling and oncogenic activity.
  • K-Ras4B, frequently mutated in cancers, relies on electrostatic interactions for membrane binding.
  • The role of cationic amphiphilic drugs in modulating Ras protein membrane association is not fully understood.

Purpose of the Study:

  • To investigate the effects of chlorpromazine (CPZ) on the membrane association of oncogenic K-Ras(G12V).
  • To determine how CPZ influences K-Ras(G12V) mediated cell proliferation and apoptosis.
  • To elucidate the mechanism by which CPZ affects K-Ras(G12V) membrane dynamics.

Main Methods:

  • Live cell microscopy
  • Fluorescence Recovery After Photobleaching (FRAP) beam size analysis
  • Cell fractionation studies
  • Analysis of related proteins Rac1(G12V) and H-Ras

Main Results:

  • CPZ significantly reduces the plasma membrane association of GFP-K-Ras(G12V).
  • CPZ increases the exchange rate of GFP-K-Ras(G12V) between plasma membrane and cytoplasmic pools.
  • CPZ-induced K-Ras(G12V) mislocalization results in cell cycle arrest or apoptosis, and compromises cancer cell transformed phenotypes.

Conclusions:

  • CPZ disrupts K-Ras(G12V) membrane anchorage through electrostatic interactions.
  • CPZ-induced disruption of K-Ras(G12V) localization triggers cell death pathways and inhibits cancer cell proliferation and migration.
  • CPZ shows potential as a therapeutic agent targeting oncogenic K-Ras signaling.

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