Human tumor nanoparticles induce apoptosis of pancreatic cancer cells.
Exosomes are vesicles secreted by most hematopoietic cells on fusion of multivesicular endosomes with the plasma membrane. Many studies have reported that exosomes may also be released by tumor cells. Exosomes are believed to play an antitumor role through immune cells. We asked whether tumor exosomes have biological activities on tumor cells. We report that human pancreatic tumor nanoparticles, exosome-like as characterized by proteomic analyses and rich in lipid rafts, decreased tumor cell proliferation. Nanoparticles increased Bax and decreased Bcl-2 expressions. Caspase-3 and -9 but not caspase-8 inhibitors impaired apoptosis, which implicates the mitochondria apoptotic pathway. The ceramide-sphingomyelin apoptotic pathway was inoperative. Moreover, nanoparticles induced phosphatase and tensin homolog (PTEN) and glycogen synthase kinase (GSK) -3beta activation and decreased pyruvate dehydrogenase activity. In nanoparticle-treated cells, PTEN formed complexes with actin, beta-catenin, and GSK-3beta. Thus, beta-catenin may no longer be available to activate the survival pathway. Nanoparticles triggered the down-regulation of cyclin D1 and poly(ADP-ribose) polymerase. Hence, nanoparticles counteracted the constitutively activated phosphatidylinositol 3-kinase/Akt survival pathway to drive tumor cells toward apoptosis. Our study provides the first evidence of an apoptotic function of tumor-derived nanoparticles on tumor cells. We propose a new role for nanoparticles, i.e., as signal carriers for interaction between cells, which may have implications in physiopathological situations.
INSERM UMR 911; Aix-Marseille Université, Marseille, France.
Elodie
E
Ristorcelli
Evelyne
E
Beraud
Patrick
P
Verrando
Claude
C
Villard
Daniel
D
Lafitte
Véronique
V
Sbarra
Dominique
D
Lombardo
Alain
A
Verine
D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002518:Ceramides / Q000502:physiology; D011992:Endosomes / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008055:Lipids / Q000032:analysis; D021962:Membrane Microdomains / Q000502:physiology; D053758:Nanoparticles; D009363:Neoplasm Proteins / Q000032:analysis; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
D061945:Caspase Inhibitors; D002518:Ceramides; D008055:Lipids; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011768:Pyruvate Dehydrogenase Complex; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase