Histone deacetylase inhibitors induced caspase-independent apoptosis in human pancreatic adenocarcinoma cell lines.
The antitumor activity of the histone deacetylase inhibitors was tested in three well-characterized pancreatic adenocarcinoma cell lines, IMIM-PC-1, IMIM-PC-2, and RWP-1. These cell lines have been previously characterized in terms of their origin, the status of relevant molecular markers for this kind of tumor, resistance to other antineoplastic drugs, and expression of differentiation markers. In this study, we report that histone deacetylase inhibitors induce apoptosis in pancreatic cancer cell lines, independently of their intrinsic resistance to conventional antineoplastic agents. The histone deacetylase inhibitor-induced apoptosis is due to a serine protease-dependent and caspase-independent mechanism. Initially, histone deacetylase inhibitors increase Bax protein levels without affecting Bcl-2 levels. Consequently, the apoptosis-inducing factor (AIF) and Omi/HtrA2 are released from the mitochondria, with the subsequent induction of the apoptotic program. These phenomena require AIF relocalization into the nuclei to induce DNA fragmentation and a serine protease activity of Omi/HtrA2. These data, together with previous results from other cellular models bearing the multidrug resistance phenotype, suggest a possible role of the histone deacetylase inhibitors as antineoplastic agents for the treatment of human pancreatic adenocarcinoma.
García-Morales
Pilar
P
Instituto de Biologia Molecular y Celular, Ed. Torregaitan, Universidad Miguel Hernandez, 03202 Elche (Alicante), Spain.
Gómez-Martínez
Angeles
A
Carrato
Alfredo
A
Martínez-Lacaci
Isabel
I
Barberá
Víctor M
VM
Soto
José L
JL
Carrasco-García
Estefanía
E
Menéndez-Gutierrez
María P
MP
Castro-Galache
María D
MD
Ferragut
José A
JA
Saceda
Miguel
M
D000230:Adenocarcinoma / Q000737:chemistry / Q000201:enzymology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005420:Flavoproteins / Q000032:analysis / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000201:enzymology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D000077337:Vorinostat; D051028:bcl-2-Associated X Protein
C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; C494826:BAX protein, human; D004791:Enzyme Inhibitors; D005420:Flavoproteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C012589:trichostatin A; D000077337:Vorinostat; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020169:Caspases