Palmatine suppresses glutamine-mediated interaction between pancreatic cancer and stellate cells through simultaneous inhibition of survivin and COL1A1. (10th April 2018)

• Record Type: Journal Article
• Authors: Chakravarthy, Divya; Muñoz, Amanda R.; Su, Angel; Hwang, Rosa F.; Keppler, Brian R.; Chan, Daniel E.; Halff, Glenn; Ghosh, Rita; Kumar, Addanki P.
• Is Part Of: Cancer letters. Volume 419(2018)
• Page Start: 103
• Page End: 115
• Publication Date: 2018-04-10
• Subjects: GLI signaling -- Palmatine -- Pancreatic cancer -- Desmoplasia -- glutamine; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.01.057
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Desmoplasia, a key feature of pancreatic cancer, a major impediment to efficient drug delivery and therapeutic resistance. Glutamine mediates communication between stellate and cancer cells. Palmatine inhibits stellate-cancer cell communication in part through changes in GLI, COL1A1 and survivin signaling. Inhibiting growth and interaction between pancreatic tumor cells and stellate cells can potentiate Gemcitabine activity. Palmatine enhances gemcitabine activity and inhibits growth of gemcitabine resistant cells.