@article{90869cb9cd0542158ad06438ed49adbd,
title = "Palmatine suppresses glutamine-mediated interaction between pancreatic cancer and stellate cells through simultaneous inhibition of survivin and COL1A1",
abstract = "Reciprocal interaction between pancreatic stellate cells (PSCs) and cancer cells (PCCs) in the tumor microenvironment (TME) promotes tumor cell survival and progression to lethal, therapeutically resistant pancreatic cancer. The goal of this study was to test the ability of Palmatine (PMT) to disrupt this reciprocal interaction in vitro and examine the underlying mechanism of interaction. We show that PSCs secrete glutamine into the extracellular environment under nutrient deprivation. PMT suppresses glutamine-mediated changes in GLI signaling in PCCs resulting in the inhibition of growth and migration while inducing apoptosis by inhibition of survivin. PMT-mediated inhibition of (glioma-associated oncogene 1) GLI activity in stellate cells leads to suppression (collagen type 1 alpha 1) COL1A1 activation. Remarkably, PMT potentiated gemcitabine's growth inhibitory activity in PSCs, PCCs and inherently gemcitabine-resistant pancreatic cancer cells. This is the first study that shows the ability of PMT to inhibit growth of PSCs and PCCs either alone or in combination with gemcitabine. These studies warrant additional investigations using preclinical models to develop PMT as an agent for clinical management of pancreatic cancer.",
keywords = "Desmoplasia, GLI signaling, Palmatine, Pancreatic cancer, glutamine",
author = "Divya Chakravarthy and Mu{\~n}oz, {Amanda R.} and Angel Su and Hwang, {Rosa F.} and Keppler, {Brian R.} and Chan, {Daniel E.} and Glenn Halff and Rita Ghosh and Kumar, {Addanki P.}",
note = "Funding Information: Funding: This work was supported in part by the funds from Veterans Affairs-Merit Award I01 BX 000766-01 and BX003876 ; National Center for Complementary and Alternate Medicine 1R01 AT007448 (APK) and National Cancer Institute R01 CA 149516 (RG) . Funding Information: We acknowledge support provided by CTRC at UTHSA through the NCI support grant #2P30 CA 054174-17 (APK) and the CTRC 40 th Anniversary Distinguished Professor of Oncology Endowment (APK). The authors acknowledge the support provided by Flow Cytometry Core Facility at UTHSA . Human PSCs; hTERT-HPNE pancreatic cells modified to express oncogenic KRAS (referred to as HPNE-Ras) and GLI-Luc reporter plasmid were generous gifts from Drs. Rosa F. Hwang (University of Texas MD Anderson Cancer Center); James W. Freeman (University of Texas Health San Antonio) and Lu Zhe Sun (University of Texas Health San Antonio) respectively. Funding Information: Funding: This work was supported in part by the funds from Veterans Affairs-Merit Award I01 BX 000766-01 and BX003876; National Center for Complementary and Alternate Medicine 1R01 AT007448 (APK) and National Cancer Institute R01 CA 149516 (RG). Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = apr,
day = "10",
doi = "10.1016/j.canlet.2018.01.057",
language = "English (US)",
volume = "419",
pages = "103--115",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
}