Interruption of RNA processing machinery by a small compound, 1-[(4-chlorophenyl)methyl]-1H-indole-3-carboxaldehyde (oncrasin-1)

Protein kinase C iota (PKC iota) is activated by oncogenic Ras proteins and is required for K-Ras-induced transformation and colonic carcinogenesis in vivo. However, the role of PKC iota in signal transduction and oncogenesis is not clear. We recently identified a small molecule, designated 1-[(4-chlorophenyl)methyl]-1H-indole-3-carboxaldehyde (oncrasin-1), that can selectively kill K-Ras mutant cancer cells and induce abnormal nuclear aggregation of PKC iota in sensitive cells but not in resistant cells. To determine the causes and biological consequences of PKC iota aggregates in the nucleus, we analyzed the effect of oncrasin-1 on proteins involved in DNA repair and RNA processing. Our results showed that oncrasin-1 treatment led to coaggregation of PKC iota and splicing factors into megaspliceosomes but had no obvious effects on the DNA repair molecule Rad51. Moreover, oncrasin-1 treatment suppressed the phosphorylation of the largest subunit of RNA polymerase II and the expression of intronless reporter genes in sensitive cells but not in resistant cells, suggesting that suppression of RNA transcription is a major effect of oncrasin-1 treatment. Studies with cultured cells or with recombinant proteins showed that oncrasin-1 can disrupt the interaction of PKC iota and cyclin-dependent protein kinase 9/cyclin T1 complex, which is known to phosphorylate the largest subunit of RNA polymerase 11 and is required for RNA transcription. Together, our results suggest that oncrasin-1 suppresses the function of RNA processing machinery and that PKC iota might be involved in the biological function of RNA processing complexes. [Mol Cancer Ther 2009;8(2):441-8]