Mammalian intracellular ribonuclease L (RNase L) is a latent endoribonuclease that functions against viral infections as an apoptosis-inducing protein, and its activity requires intracellular 5′-end-triphosphorylated-2′,5′ oligoadenylates (2-5A) as an activator. Previously, we showed that RNase L can be activated in human cancer cell line HT1080 by an RNA polymerase I inhibitor, 1-(3-C-ethynyl-β-d-ribo-pentofuranosyl)cytosine (3′-ethynylcytidine; ECyd). In ECyd-treated cells, knockdown of the RNase L resulted in a marked decrease in c-jun N-terminal kinase (JNK) phosphorylation, thereby inhibiting apoptosis. We investigate RNase L binding partners by focused proteomic approach using immunoprecipitation with anti-RNase L IgG and mass spectrometry. We found that the IQ motif-containing Ras GTPase-activating-like protein 1 (IQGAP1) can associate with RNase L, and that phosphorylation occurs on the IQGAP1. ECyd-induced JNK phosphorylation and apoptosis were inhibited when IQGAP1 was knocked down with a small interfering RNA. These results raise the interesting possibility that the RNase L–IQGAP1 association may regulate JNK phosphorylation in RNase L-madiated apoptosis. It is likely IQGAP1 works as a regulator in apoptosis. Structured digital abstract • MINT-7990574: RNaseL (uniprotkb:Q05823) physically interacts (MI:0914) with Kinesin-like protein KIF23 (uniprotkb:Q02241) and Ras GTPase-activating-like protein IQGAP1 (uniprotkb:P46940) by anti bait coimmunoprecipitation (MI:0006) • MINT-7990598: RNaseL (uniprotkb:Q05823) physically interacts (MI:0915) with IQGAP1 (uniprotkb:P46940) by anti bait coimmunoprecipitation (MI:0006)

Cell death can be broadly characterized as either necrosis or apoptosis, depending on the morphological and biochemical features of the cell itself. We have previously reported that the treatment of mouse mammary carcinoma FM3A cells with the anticancer drug floxuridine (FUdR) induces necrosis in the original clone F28-7 but apoptosis in the variant F28-7-A. We have identified regulators, including heat shock protein 90, lamin-B1, cytokeratin-19, and activating transcription factor 3, of cell death mechanisms by using comprehensive gene and protein expression analyses and a phenotype-screening approach. We also observed that the individual inhibition or knockdown of the identified regulators in F28-7 results in a shift from necrotic to apoptotic morphology. Furthermore, we investigated microRNA (miRNA, miR) expression profiles in sister cell strains F28-7 and F28-7-A using miRNA microarray analyses. We found that several unique miRNAs, miR-351-5p and miR-743a-3p, were expressed at higher levels in F28-7-A than in F28-7. Higher expression of these miRNAs in F28-7 induced by transfecting miR mimics resulted in a switch in the mode of cell death from necrosis to apoptosis. Our findings suggest that the identified cell death regulators may play key roles in the decision of cell death mechanism: necrosis or apoptosis.

Aqueous extracts of 6 traditional Korean medicines used to treat malaria were tested in vitro for their antimalarial activity against Plasmodium falciparum. The EC50 values for the herbal extracts were in the range 1.4—8.1 μg/ml. Significant antimalarial activity was observed with Coptis japonica (EC50=1.4 μg/ml), but it demonstrated no selective toxicity (selectivity=1). In contrast, Kalopanax pictus showed antimalarial activity (EC50=4.6 μg/ml) and higher selective toxicity (>4). This indicated that K. pictus may be potent for a new antimalarial agent.