SIRT2, a nicotinamide adenine dinucleotide
+-dependent deacetylase, has been proposed to be a tumor suppressor associated with aging, the cell cycle, and carcinogenesis [
36]. SIRT2 knockout mice develop cancers in multiple organs via aurora-A and -B that direct centrosome amplification, aneuploidy, and mitotic cell death [
4]. However, SIRT2 mRNA levels are significantly elevated in AML blasts [
6]. SIRT2-overexpressing cells also exhibit prolongation of the cell cycle [
37]. SIRT2 activity in glioma cells is required for survival [
38]. Furthermore, SIRT2 downregulation using siRNA causes apoptosis of HeLa cells [
39]. Therefore, SIRT2 inhibitors are emerging as antitumor drugs [
40]. Here, SIRT2 protein expression in leukemic cell lines indicated that SIRT2 is a target for treatment of leukemia (Fig.
2). We have developed specific SIRT2 inhibitors NCO-90 and NCO-141 [
22]. NCO-90/141 inhibited cell growth of leukemic cell lines including HTLV-1-transformed T cells by apoptosis and CICD (Figs.
2,
3,
4,
5 and
6). Selective SIRT2 inhibitors induce cell death in non-small cell lung cancer and breast cancer cell lines [
41,
42]. Thus, SIRT2 inhibitors are promising lead candidates for use in cancer treatments. However, studies of SIRT2 functions in cancers have obtained contradictory results, indicating that further studies will be required to estimate the therapeutic potential of targeting SIRT2 in cancer [
1,
36,
43].
In this study, a caspase inhibitor did not prevent NCO-90/141-induced cell death, indicating that NCO-90/141 induced CICD (Figs.
5 and
6). Under the conditions of CICD, glyceraldehyde-3-phosphate dehydrogenase in glycolysis participates in transcriptional upregulation of ATG12 and enhances autophagy [
34]. Furthermore, caspase inhibition often leads to autophagic cell death when caspase inhibition does not inhibit cell death [
33]. Autophagy is the regulated and destructive mechanism by which long-lived proteins, organelles, and protein aggregates are captured within autophagosomes [
44‐
46]. Here, we found that NCO-90/141 inhibited the growth of leukemic cell lines and increased LC3-II levels by mitochondrial superoxide generation and caspase activation (Figs.
4 and
8). Autophagy caused by NCO-90/141 may induce degradation of p53. SIRT2 interferes with autophagy-mediated degradation of protein aggregates in neuronal cells under proteasome inhibition [
47]. SIRT2 knockdown also increases basal autophagy [
48]. Mitochondrial outer membrane permeabilization triggers the removal of permeabilized mitochondria by the autophagic machinery [
49]. Thus, SIRT2 inhibition induces autophagy by mitochondrial superoxide generation. Furthermore, NCO-90/141-induced cell death was not inhibited in combination with bafilomycin A, an autophagy flux inhibitor, for 72 h (data not shown). Therefore, these results suggest that the molecules involved in caspase-independent DNA fragmentation may augment caspase activity, and secondary caspase activation and autophagy induced by NCO-90/141 may be the result, but not the cause, of cell death.