Polyisoprenylated methylated protein methyl esterase: A putative biomarker and therapeutic target for pancreatic cancer

Abstract

Pancreatic cancer is the most deadly neoplasm with a 5-year survival rate of less than 6%. Over 90% of cases harbor K-Ras mutations, which are the most challenging to treat due to lack of effective therapies. Here, we reveal that polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in 93% of pancreatic ductal adenocarcinoma. We further present polyisoprenylated cysteinyl amide inhibitors (PCAIs) as novel compounds designed with structural elements for optimal in vivo activities and selective disruption of polyisoprenylation-mediated protein functions. The PCAIs inhibited PMPMEase with Ki values ranging from 3.7 to 20 µM. The 48 h EC50 values for pancreatic cancer Mia PaCa-2 and BxPC-3 cell lines were as low as 1.9 µM while salirasib and farnesylthiosalicylamide were ineffective at 20 µM. The PCAIs thus have the potential to serve as effective therapies for pancreatic and other cancers with hyperactive growth signaling pathways mediated by Ras and related G-proteins.

Polyisoprenylated cysteinyl amide inhibitors disrupt actin cytoskeleton organization, induce cell rounding and block migration of non-small cell lung cancer

“…We previously reported the synthesis of polyisoprenylated cysteinyl amide inhibitors (PCAIs) for testing as potential anti-cancer agents [ 20 ]. PCAIs were designed to target polyisoprenylated methylated protein methyl esterase (PMPMEase), an enzyme which is overexpressed and hyperactive in lung cancer cells and tissues [ 20 , 21 ].…”

“…We previously reported the synthesis of polyisoprenylated cysteinyl amide inhibitors (PCAIs) for testing as potential anti-cancer agents [ 20 ]. PCAIs were designed to target polyisoprenylated methylated protein methyl esterase (PMPMEase), an enzyme which is overexpressed and hyperactive in lung cancer cells and tissues [ 20 , 21 ]. We demonstrated that PCAIs are poor inhibitors of PMPMEase but potent inhibitors of cell viability, cell proliferation, and apoptosis in pancreatic cancer cells [ 20 ].…”

“…PCAIs were designed to target polyisoprenylated methylated protein methyl esterase (PMPMEase), an enzyme which is overexpressed and hyperactive in lung cancer cells and tissues [ 20 , 21 ]. We demonstrated that PCAIs are poor inhibitors of PMPMEase but potent inhibitors of cell viability, cell proliferation, and apoptosis in pancreatic cancer cells [ 20 ]. The effects of PCAIs on Rho protein function, F-actin assembly and organization, cell migration and invasion have not yet been demonstrated in NSCLC.…”

Polyisoprenylated Cysteinyl Amide Inhibitors Deplete K-Ras and Induce Caspase-dependent Apoptosis in Lung Cancer Cells

“…PCAIs (NSL-BA-036, NSL-BA-040, NSL-BA-055 and NSL-BA-056) were synthesized in our lab as previously described [23]. CellTiter-Blue Cell Viability Assay kit, Caspase-Glo 3/7, Caspase-Glo 8 and Caspase-Glo 9 Assay kits were obtained from Promega.…”

“…The lack of effective therapies against cancers driven by mutant Ras proteins coupled with the aggressiveness of such tumors maintains the impetus for the continuous search for novel therapies. This drive led us to develop the polyisoprenylated cysteinyl amide inhibitors (PCAIs) initially to suppress the activities of PMPMEase (Aguilar, Nkembo et al 2014) which we found to be overexpressed in lung and pancreatic cancers [22,23]. Remarkably, we observed that although the PCAIs only minimally inhibited PMPMEase [23], their potencies against cell viability and proliferation, angiogenesis, migration and invasion vastly surpassed their PMPMEase inhibition [24–27].…”