Cannabidiol (CBD) is the main compound present in non-psychoactive or fibre-type Cannabis sativa L., commonly known as hemp. Recent studies revealed that it inhibits the proliferation of human chronic myelogenous leukaemia cell line K562. In particular, CBD induces apoptosis by the release of cytochrome c in the cytosol together with the decrease of the mitochondrial membrane potential and the activation of caspase 3 and 7. To shed light on CBD apoptotic mechanism of action, we identified its interactome in K562 cells by a functional proteomic approach called “Drug Affinity Responsive Target Stability” (DARTS). It relies on the target protection conferred by ligand interaction against proteolysis. DARTS results were, then, validated by immunoblotting and targeted-Limited Proteolysis-Multiple Reaction Monitoring Mass spectrometry (t-LiP-MRM). This strategy allows the recognition of the target/ligand interaction peptides looking at the protein conformational alterations due to the small molecule binding, without any purification of the protein itself in a whole cell lysate. Our proteomic platform revealed the 116 kDa U5 small nuclear ribonucleoprotein component (EFTUD2), a highly conserved spliceosomal GTPase, as a CBD novel biological target. It has been showed that the peptides protected by CBD (S[183-194]K and I[326-341]K) belong to the GTP binding domain of EFTUD2. EFTUD2 is reported in literature as an oncogene that promotes the survival of several cancer cells through the activation of STAT3, which is known to be inhibited by CBD. Thus, on the basis of this, we conclude that CBD apoptotic effects on K562 cell lines are possibly due to its ability to affect the GTPase activity of EFTUD2.

Proteomics-aided insight on cannabidiol action mechanism on chronic myelogenous leukemia cancer cells

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