Information is lacking on the effects toxic environmental metals may have on the
26S proteasome. The
proteasome is a primary vehicle for selective degradation of damaged
proteins in a cell and due to its role in cell proliferation, inhibition of the
proteasome has become a target for
cancer therapy. Metals are essential to the
proteasome's normal function and have been used within
proteasome-inhibiting complexes for
cancer therapy. This study evaluated the association of erythrocyte
metal levels and
proteasome chymotrypsin-like (CT-like) activity in age- and race-matched
prostate cancer cases (n=61) and controls (n=61). Erythrocyte metals were measured by inductively coupled plasma mass spectrometry (ICP-MS). CT-like activity was measured by
proteasome activity assay using a fluorogenic
peptide substrate. Among cases, significant correlations between individual toxic metals were observed (r(
arsenic-
cadmium)=0.49, p<0.001; r(
arsenic-lead)=0.26, p=0.04, r(
cadmium-lead) 0.53, p<0.001), but there were no significant associations between metals and CT-like activity. In contrast, within controls there were no significant associations between metals, however,
copper and lead levels were significantly associated with CT-like activity. The associations between
copper and lead and
proteasome activity (r(
copper-CT-like)=-0.28, p=0.002 ; r(lead-CT-like)=0.23, p=0.011) remained significant in multivariable models that included all of the metals. These findings suggest that biologically essential metals and toxic metals may affect
proteasome activity in healthy controls and, further, show that
prostate cancer cases and controls differ in associations between metals and
proteasome activity in erythrocytes. More research on toxic metals and the
proteasome in
prostate cancer is warranted.