Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells.
Autophagy can promote cell survival or cell death, but the molecular basis underlying its dual role in cancer remains obscure. Here we demonstrate that delta(9)-tetrahydrocannabinol (THC), the main active component of marijuana, induces human glioma cell death through stimulation of autophagy. Our data indicate that THC induced ceramide accumulation and eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation and thereby activated an ER stress response that promoted autophagy via tribbles homolog 3-dependent (TRB3-dependent) inhibition of the Akt/mammalian target of rapamycin complex 1 (mTORC1) axis. We also showed that autophagy is upstream of apoptosis in cannabinoid-induced human and mouse cancer cell death and that activation of this pathway was necessary for the antitumor action of cannabinoids in vivo. These findings describe a mechanism by which THC can promote the autophagic death of human and mouse cancer cells and provide evidence that cannabinoid administration may be an effective therapeutic strategy for targeting human cancers.
Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain.
María
M
Salazar
Arkaitz
A
Carracedo
Iñigo J
IJ
Salanueva
Sonia
S
Hernández-Tiedra
Mar
M
Lorente
Ainara
A
Egia
Patricia
P
Vázquez
Cristina
C
Blázquez
Sofía
S
Torres
Stephane
S
García
Jonathan
J
Nowak
Gian María
GM
Fimia
Mauro
M
Piacentini
Francesco
F
Cecconi
Pier Paolo
PP
Pandolfi
Luis
L
González-Feria
Juan L
JL
Iovanna
Manuel
M
Guzmán
Patricia
P
Boya
Guillermo
G
Velasco
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D013759:Dronabinol / Q000494:pharmacology / Q000627:therapeutic use; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000037:antagonists & inhibitors; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000590:Amino Acid Chloromethyl Ketones; D051792:Basic Helix-Loop-Helix Proteins; D002186:Cannabinoids; D053148:Caspase 3; D018797:Cell Cycle Proteins; D013759:Dronabinol; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D000076222:Mechanistic Target of Rapamycin Complex 1; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C477012:MAP1LC3A protein, human; C491643:NUPR1 protein, human; C474831:TRIB3 protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone