Polyisoprenylated methylated protein methyl esterase is both sensitive to curcumin and overexpressed in colorectal cancer: implications for chemoprevention and treatment.
Inhibition of PMPMEase, a key enzyme in the polyisoprenylation pathway, induces cancer cell death. In this study, purified PMPMEase was inhibited by the chemopreventive agent, curcumin, with a K(i) of 0.3 μM (IC50 = 12.4 μM). Preincubation of PMPMEase with 1 mM curcumin followed by gel-filtration chromatography resulted in recovery of the enzyme activity, indicative of reversible inhibition. Kinetics analysis with N-para-nitrobenzoyl-S-trans,trans-farnesylcysteine methyl ester substrate yielded K M values of 23.6 ± 2.7 and 85.3 ± 15.3 μM in the absence or presence of 20 μM curcumin, respectively. Treatment of colorectal cancer (Caco2) cells with curcumin resulted in concentration-dependent cell death with an EC50 of 22.0 μg/mL. PMPMEase activity in the curcumin-treated cell lysate followed a similar concentration-dependent profile with IC50 of 22.6 μg/mL. In colorectal cancer tissue microarray studies, PMPMEase immunoreactivity was significantly higher in 88.6% of cases compared to normal colon tissues (P < 0.0001). The mean scores ± SEM were 91.7 ± 11.4 (normal), 75.0 ± 14.4 (normal adjacent), 294.8 ± 7.8 (adenocarcinoma), and 310.0 ± 22.6 (mucinous adenocarcinoma), respectively. PMPMEase overexpression in colorectal cancer and cancer cell death stemming from its inhibition is an indication of its possible role in cancer progression and a target for chemopreventive agents.
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Felix
F
Amissah
Randolph
R
Duverna
Byron J
BJ
Aguilar
Rosemary A
RA
Poku
Nazarius S
NS
Lamango
D018938:Caco-2 Cells; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D003474:Curcumin / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D058990:Molecular Targeted Therapy; D017368:Protein Prenylation / Q000235:genetics*
D002265:Carboxylic Ester Hydrolases; C042523:protein methylesterase; D003474:Curcumin