Polyisoprenylated Methylated Protein Methyl Esterase Is Both Sensitive to Curcumin and Overexpressed in Colorectal Cancer: Implications for Chemoprevention and Treatment

Abstract

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.

Characterization of Gene Expression Patterns among Artificially Developed Cancer Stem Cells Using Spherical Self-Organizing Map

“… 55 This gene is highly expressed in human colorectal cancers. 56 These molecules are thought to be positively correlated with cancer. On the other hand, AHNAK is expressed in various cell types and involved in many cellular processes such as calcium regulation and actin organization.…”

ecancermedicalscience

“…In recognition of this and the ubiquitous nature of polyisoprenylated proteins, we examined the expression of PMPMEase in CaP tissues and cell lines. The observation that PMPMEase is hyperactive and overexpressed in CaP cell lines and that 87% of CaP cases is congruent with the effects of PMPMEase inhibition on cell viability not only on the CaP cells, but also in the lungs [25, 51] and colorectal cancer cell lines [24]. These results have a direct bearing on such aspects of cancer biology as proliferation and metastasis, given the biological functions of PMPMEase putative protein substrates on cell viability and migration.…”

“…These findings, in addition to the roles that polyisoprenylated proteins play in cancer progression led us to hypothesise that PMPMEase may be hyperactive in cancers. This suspicion was recently confirmed when PMPMEase was found to be overexpressed in 86.6% of colorectal cancer cases [24]. In recognition of this and the ubiquitous nature of polyisoprenylated proteins, we examined the expression of PMPMEase in CaP tissues and cell lines.…”

“…This resulted in a single esterase that was identified as the porcine ortholog of human carboxylesterase 1 (hCE1) [28]. We later found that chemopreventive food-derived substances that inhibit the enzyme had profound inhibitory effects on the viability of cancer cells [24, 25]. These findings, in addition to the roles that polyisoprenylated proteins play in cancer progression led us to hypothesise that PMPMEase may be hyperactive in cancers.…”

“…The human TMAs used in the studies were supplied by, and the immunohistochemistry conducted at US Biomax (Rockville, MD, USA). These were probed and analysed for PMPMEase (human carboxylesterase 1, hCE1) as described previously [24]. …”