title: Curcumin Modulates Pancreatic Adenocarcinoma Cell-Derived Exosomal Function.
abstract: Pancreatic cancer has the highest mortality rates of all cancer types. One potential explanation for the aggressiveness of this disease is that cancer cells have been found to communicate with one another using membrane-bound vesicles known as exosomes. These exosomes carry pro-survival molecules and increase the proliferation, survival, and metastatic potential of recipient cells, suggesting that tumor-derived exosomes are powerful drivers of tumor progression. Thus, to successfully address and eradicate pancreatic cancer, it is imperative to develop therapeutic strategies that neutralize cancer cells and exosomes simultaneously. Curcumin, a turmeric root derivative, has been shown to have potent anti-cancer and anti-inflammatory effects in vitro and in vivo. Recent studies have suggested that exosomal curcumin exerts anti-inflammatory properties on recipient cells. However, curcumin's effects on exosomal pro-tumor function have yet to be determined. We hypothesize that curcumin will alter the pro-survival role of exosomes from pancreatic cancer cells toward a pro-death role, resulting in reduced cell viability of recipient pancreatic cancer cells. The main objective of this study was to determine the functional alterations of exosomes released by pancreatic cancer cells exposed to curcumin compared to exosomes from untreated pancreatic cancer cells. We demonstrate, using an in vitro cell culture model involving pancreatic adenocarcinoma cell lines PANC-1 and MIA PaCa-2, that curcumin is incorporated into exosomes isolated from curcumin-treated pancreatic cancer cells as observed by spectral studies and fluorescence microscopy. Furthermore, curcumin is delivered to recipient pancreatic cancer cells via exosomes, promoting cytotoxicity as demonstrated by Hoffman modulation contrast microscopy as well as AlamarBlue and Trypan blue exclusion assays. Collectively, these data suggest that the efficacy of curcumin may be enhanced in pancreatic cancer cells through exosomal facilitation.
authors.affiliation: Division of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, California, United States of America.
authors.forename: Carlos J Diaz
authors.initials: CJ
authors.lastname: Osterman
authors.affiliation: Division of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, California, United States of America.
authors.forename: James C
authors.initials: JC
authors.lastname: Lynch
authors.affiliation: Division of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, California, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Leaf
authors.affiliation: Department of Anatomy, Loma Linda University School of Medicine, Loma Linda, California, United States of America.
authors.forename: Amber
authors.initials: A
authors.lastname: Gonda
authors.affiliation: Division of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, California, United States of America.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Ferguson Bennit
authors.affiliation: Malvern Instruments Inc., Rancho Cucamonga, California, United States of America.
authors.forename: Duncan
authors.initials: D
authors.lastname: Griffiths
authors.affiliation: Division of Biochemistry, Center for Health Disparities and Molecular Medicine, Loma Linda University, Loma Linda, California, United States of America.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Wall
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D003474:Curcumin