Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice.

Andrew K Kwegyir-Afful,Vincent C.O Njar,Puranik Purushottamachar,Marlena S Martin,Vidya P Ramamurthy,Francis N Murigi

doi:10.18632/oncotarget.14154

Andrew K Kwegyir-Afful, Vincent C.O Njar + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.14154

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Abstract

Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-κB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC. Galeterone (gal), a multi-target, agent in phase III clinical development for prostate cancer has also shown effects on the aforementioned pathways. We show for the first time, that gal/analogs (VNPT55, VNPP414 and VNPP433-3β) profoundly inhibited cell viability of gemcitabine-naive/resistance PDAC cell lines and strongly synergized with gemcitabine in gemcitabine-resistant PDAC cells. In addition, to inducing G1 cell cycle arrest, gal/analogs induced caspase 3-mediated cell-death of PDAC cells. Gal/analogs caused profound downregulation of Mnk1/2, peIF4E and NF-κB (p-p65), metastatic inducing factors (N-cadherin, MMP-1/-2/-9, Slug, Snail and CXCR4) and putative stem cell factors, (β-Catenin, Nanog, BMI-1 and Oct-4). Gal/analog also depleted EZH2 and upregulated E-Cadherin. These effects resulted in significant inhibition of PDAC cell migration, invasion and proliferation. Importantly, we also observed strong MiaPaca-2 tumor xenograft growth inhibition (61% to 92%). Collectively, these promising findings strongly support further development of gal/analogs as novel therapeutics for PDAC.

Highlights

IntroductionPancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is a highly aggressive epithelial cancer with a reported 5-year survival rate of ~5% [1]
Pancreatic cancer is a highly aggressive epithelial cancer with a reported 5-year survival rate of ~5% [1]
Survival rate for pancreatic cancer is poor, with about 80% of patients presenting with the metastatic disease

Summary

Introduction

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is a highly aggressive epithelial cancer with a reported 5-year survival rate of ~5% [1]. Mutant K-RAS oncogene constitutively activates the MAPK pathway as well as the PI3K/Akt/mTOR pathway, which are known to promote growth and development of PDAC [4, 5]. These two signaling pathways converge downstream at the eukaryotic translational initiation complex, eIF4F, which mediates cap-dependent mRNA translational initiation apparatus critical for eukaryotic protein synthesis [6,7,8]. Phosphorylation of eIF4E at serine 209 by the MAPK interacting kinases Mnk1/2 [9, 10] is a ratewww.impactjournals.com/oncotarget limiting step in the formation of the eIF4F complex preceding mRNA translation. Inhibitors targeting the Mnk1/2-eIF4E axis are actively under investigation for the treatment of several cancers [13]

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