A critical role of autophagy in antileukemia/lymphoma effects of APO866, an inhibitor of NAD biosynthesis.
APO866, an inhibitor of NAD biosynthesis, exhibits potent antitumor properties in various malignancies. Recently, it has been shown that APO866 induces apoptosis and autophagy in human hematological cancer cells, but the role of autophagy in APO866-induced cell death remains unclear. Here, we report studies on the molecular mechanisms underlying APO866-induced cell death with emphasis on autophagy. Treatment of leukemia and lymphoma cells with APO866 induced both autophagy, as evidenced by an increase in autophagosome formation and in SQSTM1/p62 degradation, but also increased caspase activation as revealed by CASP3/caspase 3 cleavage. As an underlying mechanism, APO866-mediated autophagy was found to deplete CAT/catalase, a reactive oxygen species (ROS) scavenger, thus promoting ROS production and cell death. Inhibition of autophagy by ATG5 or ATG7 silencing prevented CAT degradation, ROS production, caspase activation, and APO866-induced cell death. Finally, supplementation with exogenous CAT also abolished APO866 cytotoxic activity. Altogether, our results indicated that autophagy is essential for APO866 cytotoxic activity on cells from hematological malignancies and also indicate an autophagy-dependent CAT degradation, a novel mechanism for APO866-mediated cell killing. Autophagy-modulating approaches could be a new way to enhance the antitumor activity of APO866 and related agents.
Department of Fundamental Neurosciences; Faculty of Biology and Medicine; University of Lausanne; Lausanne, Switzerland.
Vanessa
V
Ginet
Department of Fundamental Neurosciences; Faculty of Biology and Medicine; University of Lausanne; Lausanne, Switzerland.
Julien
J
Puyal
Department of Fundamental Neurosciences; Faculty of Biology and Medicine; University of Lausanne; Lausanne, Switzerland.
Coralie
C
Rummel
Service and Central Laboratory of Hematology; University Hospital of Lausanne; Lausanne, Switzerland.
Dominique
D
Aubry
Service and Central Laboratory of Hematology; University Hospital of Lausanne; Lausanne, Switzerland.
Caroline
C
Breton
Service and Central Laboratory of Hematology; University Hospital of Lausanne; Lausanne, Switzerland.
Anne-Julie
AJ
Cloux
Laboratory of Glycochemistry and Asymmetric Synthesis; Swiss Federal Institute of Technology (EPFL); Batochime, Lausanne, Switzerland.
Somi R
SR
Majjigapu
Laboratory of Glycochemistry and Asymmetric Synthesis; Swiss Federal Institute of Technology (EPFL); Batochime, Lausanne, Switzerland.
Bernard
B
Sordat
Laboratory of Glycochemistry and Asymmetric Synthesis; Swiss Federal Institute of Technology (EPFL); Batochime, Lausanne, Switzerland.
Pierre
P
Vogel
Department of Experimental Medicine; Section of Biochemistry; University of Genoa; Genoa, Italy.
Santina
S
Bruzzone
Department of Internal Medicine; University of Genoa; Genoa, Italy.
Alessio
A
Nencioni
Service and Central Laboratory of Hematology; University Hospital of Lausanne; Lausanne, Switzerland.
Michel A
MA
Duchosal
Service and Central Laboratory of Hematology; University Hospital of Lausanne; Lausanne, Switzerland.
Aimable
A
Nahimana
D000178:Acrylamides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology*; D009243:NAD / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010880:Piperidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000178:Acrylamides; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D017382:Reactive Oxygen Species; D009243:NAD; C505407:CASP3 protein, human; D053148:Caspase 3
APO866; ATG; CATALASE; NAD; ROS; autophagy; leukemia; lymphoma; therapy