Restoration of sensitivity to anoikis in Ras-transformed rat intestinal epithelial cells by a Ras inhibitor

Dear Editor,

Ras proteins control key signaling pathways that regulate cell growth, migration, and survival.^1,2 Activating mutations in ras[SRS1] genes or alterations in upstream signaling components that activate Ras proteins are common in most human tumors.² The activated Ras contributes to cell transformation and maintenance of the transformed tumor phenotype.¹ This is manifested by uncontrolled growth of the tumor cells and by their ability to survive under stressful conditions such as loss of matrix attachment.^1,2 Activated Ras provides survival signals and interferes with apoptosis in tumor cells.^2,3,4 Ras regulates p19^ARF and Mdm2, which control p53, a key factor in apoptosis. Activated Ras also inhibits c-myc, which induces apoptosis in the absence of survival factors. In addition, Ras regulates NF-κB, which transcriptionally activates the expression of antiapototic members of the Bcl-2 and IAP families. Ras activates phosphoinositide 3-kinase (PI3-K) and downstream effectors, including the PKB/Akt. PI3-K positively regulates the antiapototic Bcl-2 protein while Akt inhibits the activity of Bad, a proapototic member of the Bcl-2 family, and regulates gene expression by inactivating a number of forkhead family transcription factors that can induce proapoptotic genes.^2,3,4 In view of the above findings, therapies that target Ras can be expected to induce apoptosis of tumor cells. This possibility was not examined with inhibitors that affect directly the Ras protein. We showed previously that farnesylthiosalicylic acid (FTS) is a direct Ras inhibitor.⁵ FTS removes all active Ras isoforms from the cell membrane facilitating Ras degradation.⁵ This leads to the inhibition of anchorage-dependent growth of Ras-transformed cells without cytotoxicity.⁵ Thus, the inhibition of active Ras by FTS, and presumably also the neglect of Ras survival signals, are not sufficient by themselves to induce death of transformed cells. However, because cancer cells can possess means of survival in addition to Ras activation, an additional stress might be needed to promote FTS-induced apoptosis. Here, we examined whether inhibition of Ras by FTS can induce death of Ras-transformed rat intestinal epithelial-1 (RIE-1/Ras) cells that were sensitized to apoptosis by detaching them from the matrix, a process termed anoikis.

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