A distinctive feature of
cancer is the upregulation of
sirtuin proteins.
Sirtuins are class III
NAD+-dependent deacetylases involved in cellular processes such as proliferation and protection against oxidative stress.
SIRTs 1 and 2 are also overexpressed in several types of
cancers including
non-small cell lung cancer (NSCLC).
Sirtinol, a
sirtuin (
SIRT) 1 and 2 specific inhibitor, is a recent anti-
cancer agent that is cytotoxic against several types of
cancers including NSCLC. Thus,
sirtuins 1 and 2 represent valuable targets for
cancer therapy. Recent studies show that
sirtinol functions as a tridentate
iron chelator by binding Fe3+ with 3:1 stoichiometry. However, the
biological consequences of this function remain unexplored. Consistent with preliminary literature, we show that
sirtinol can deplete intracellular labile
iron pools in both A549 and H1299
non-small cell lung cancer cells acutely. Interestingly, a temporal adaptive response occurs in A549 cells as
sirtinol enhances
transferrin receptor stability and represses
ferritin heavy chain translation through impaired
aconitase activity and apparent IRP1 activation. This effect was not observed in H1299 cells. Holo-
transferrin supplementation significantly enhanced colony formation in A549 cells while increasing
sirtinol toxicity. This effect was not observed in H1299 cells. The results highlight the fundamental genetic differences that may exist between H1299 and A549 cells and offer a novel mechanism of how
sirtinol kills NSCLC cells.