Home » Key Scientific Articles » Dissecting the different biological effects of oncogenic Ras isoforms in cancer cell lines: could stimulation ofoxidative stress be the one more weapon of H-Ras? Regulation of oxidative stress and Ras biological effects.

Dissecting the different biological effects of oncogenic Ras isoforms in cancer cell lines: could stimulation ofoxidative stress be the one more weapon of H-Ras? Regulation of oxidative stress and Ras biological effects.

Bellavia M, Gioviale MC, Damiano G, Palumbo VD, Spinelli G, Buscemi G, Lo Monte AI.

Med Hypotheses. 2012 Dec;79(6):731-4.

I.E.ME.S.T., Section of Stress, dismicrobism and intestinal diseases, Palermo, Italy.

 

Abstract

Ras proteins are small GTPase functioning as molecular switches that, in response to particular extracellular signalling, as growth factors, activate a diverse array of intracellular effector cascades regulating cell proliferation, differentiation and apoptosis. Human tumours frequently express Rasproteins (Ha-, Ki-, N-Ras) activated by point mutations which contribute to malignant phenotype, including invasiveness and angiogenesis. Despite the common signalling pathways leading to similar cellular responses, studies clearly demonstrate unique roles of the Ras family members in normal and pathological conditions and the lack of functional redundancy seems to be explainable, at least in part, by the ability of Ras isoforms to localize indifferent microdomains to plasma membrane and intracellular organelles. This different intracellular compartmentalization could help Ras isoforms to contact different downstream effectors finally leading to different biological outcomes. Interestingly, it has also been shown that Ha- and Ki-Ras exert an opposite role in regulating intracellular redox status. In this regard we suggest that H-Ras specific induction of ROS (reactive oxygen species) production could be one of the main determinants of the invasive phenotype which characterize cancer cells harbouring H-Ras mutations. In our hypothesis then, while K-Ras (not able to promote oxidative stress) could mainly contribute to cancer progression and invasiveness through activation of MAPK and PI3K, H-Ras-mediated oxidative stress could play a unique role in modulation of intercellular contacts leading to a loss of cell adhesion and eventually also to a metastatic spread.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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Additional Information

 

According to our hypothesis in fact, in our experimental model (HT-29 cells), expression of oncogenic H-Ras leads to a morphological change similar to epithelial mesenchymal transition (EMT) characterized by an altered expression of some related markers, while K-Ras expression has only a weak effect on proliferation rate; the H-Ras mediated EMT is reverted by adding an antioxidant in culture medium. Further H-Ras expression causes a drastic growth arrest of HT-29 cells followed by a rapid increase in proliferation rate and an acquired ability to form colonies (see figures below). This acquired “colony-forming” phenotype is also associated to expression of stem cell markers.

 

Dissecting the different biological effects