PKC delta and tissue transglutaminase are novel inhibitors of autophagy in pancreatic cancer cells.
Apoptosis (type I) and autophagy (type II) are both highly regulated forms of programmed cell death and play crucial roles in physiological processes such as the development, homeostasis and selective, moderate to massive elimination of cells, if needed. Accumulating evidence suggests that cancer cells, including pancreatic cancer cells, in general tend to have reduced autophagy relative to their normal counterparts and premalignant lesions, supporting the contention that defective autophagy provides resistance to metabolic stress such as hypoxia, acidity and chemotherapeutics, promotes tumor cell survival and plays a role in the process of tumorigenesis. However, the mechanisms underlying the reduced capability of undergoing autophagy in pancreatic cancer remain elusive. In a recent study, we demonstrated a novel mechanism for regulation of autophagy in pancreatic ductal carcinoma cells. We found that protein kinase C-delta (PKC delta) constitutively suppresses autophagy through induction of tissue transglutaminase (TG2). Inhibition of PKC delta/TG2 signaling resulted in significant autophagic cell death that was mediated by Beclin 1. Elevated expression of TG2 in pancreatic cancer cells has been implicated in the development of drug resistance, metastatic phenotype and poor patient prognosis. In conclusion, our data suggest a novel role of PKC delta/TG2 in regulation of autophagy, and that TG2 may serve as an excellent therapeutic target in pancreatic cancer cells.
Ozpolat
Bulent
B
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. bozpolat@mdanderson.org
Akar
Ugur
U
Mehta
Kapil
K
Lopez-Berestein
Gabriel
G
D000098:Acetophenones / Q000494:pharmacology; D001343:Autophagy / Q000502:physiology*; D001578:Benzopyrans / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins; D006801:Humans; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D011503:Transglutaminases / Q000502:physiology*
D000098:Acetophenones; D001578:Benzopyrans; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C085746:rottlerin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D051745:Protein Kinase C-delta; D019204:GTP-Binding Proteins