title: Association of metals and proteasome activity in erythrocytes of prostate cancer patients and controls.
abstract: 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.
authors.affiliation: Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA. cdudas1@hfhs.org
authors.forename: Christine
authors.initials: C
authors.lastname: Neslund-Dudas
authors.forename: Bharati
authors.initials: B
authors.lastname: Mitra
authors.forename: Ashoka
authors.initials: A
authors.lastname: Kandegedara
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Sara
authors.initials: S
authors.lastname: Schmitt
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.forename: Qiuzhi
authors.initials: Q
authors.lastname: Cui
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Rybicki
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D000328:Adult; D000368:Aged; D001151:Arsenic / Q000378:metabolism / Q000633:toxicity; D002104:Cadmium / Q000378:metabolism / Q000633:toxicity; D016022:Case-Control Studies; D002918:Chymotrypsin / Q000378:metabolism; D003300:Copper / Q000378:metabolism / Q000633:toxicity; D004781:Environmental Exposure / Q000032:analysis; D004789:Enzyme Activation; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism*; D059647:Gene-Environment Interaction; D006801:Humans; D007854:Lead / Q000378:metabolism / Q000633:toxicity; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D015999:Multivariate Analysis; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*
chemical_list: D002104:Cadmium; D007854:Lead; D003300:Copper; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D001151:Arsenic