000199906 001__ 199906
000199906 005__ 20181203023533.0
000199906 0247_ $$2doi$$a10.4161/auto.27722
000199906 022__ $$a1554-8627
000199906 02470 $$2ISI$$a000335547800006
000199906 037__ $$aARTICLE
000199906 245__ $$aA critical role of autophagy in antileukemia/lymphoma effects of APO866, an inhibitor of NAD biosynthesis
000199906 260__ $$bLandes Bioscience$$c2014$$aAustin
000199906 269__ $$a2014
000199906 300__ $$a15
000199906 336__ $$aJournal Articles
000199906 520__ $$aAPO866, 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.
000199906 6531_ $$aNAD
000199906 6531_ $$aATG
000199906 6531_ $$aCATALASE
000199906 6531_ $$aROS
000199906 6531_ $$aautophagy
000199906 6531_ $$aAPO866
000199906 6531_ $$alymphoma
000199906 6531_ $$aleukemia
000199906 6531_ $$atherapy
000199906 700__ $$uUniv Lausanne, Dept Fundamental Neurosci, Fac Biol & Med, Lausanne, Switzerland$$aGinet, Vanessa
000199906 700__ $$uUniv Lausanne, Dept Fundamental Neurosci, Fac Biol & Med, Lausanne, Switzerland$$aPuyal, Julien
000199906 700__ $$uUniv Lausanne, Dept Fundamental Neurosci, Fac Biol & Med, Lausanne, Switzerland$$aRummel, Coralie
000199906 700__ $$uUniv Lausanne Hosp, Serv & Cent Lab Hematol, Lausanne, Switzerland$$aAubry, Dominique
000199906 700__ $$uUniv Lausanne Hosp, Serv & Cent Lab Hematol, Lausanne, Switzerland$$aBreton, Caroline
000199906 700__ $$uUniv Lausanne Hosp, Serv & Cent Lab Hematol, Lausanne, Switzerland$$aCloux, Anne-Julie
000199906 700__ $$0242651$$g192493$$uSwiss Fed Inst Technol EPFL, Lab Glycochem & Asymmetr Synth, Lausanne, Switzerland$$aMajjigapu, Somi R.
000199906 700__ $$uSwiss Fed Inst Technol EPFL, Lab Glycochem & Asymmetr Synth, Lausanne, Switzerland$$aSordat, Bernard
000199906 700__ $$0240222$$g123681$$uSwiss Fed Inst Technol EPFL, Lab Glycochem & Asymmetr Synth, Lausanne, Switzerland$$aVogel, Pierre
000199906 700__ $$uUniv Genoa, Sect Biochem, Dept Expt Med, Genoa, Italy$$aBruzzone, Santina
000199906 700__ $$aNencioni, Alessio
000199906 700__ $$uUniv Lausanne Hosp, Serv & Cent Lab Hematol, Lausanne, Switzerland$$aDuchosal, Michel A.
000199906 700__ $$aNahimana, Aimable$$uUniv Lausanne Hosp, Serv & Cent Lab Hematol, Lausanne, Switzerland
000199906 773__ $$j10$$tAutophagy$$k4$$q603-617
000199906 909C0 $$xU10111$$0252076$$pLGSA
000199906 909CO $$pSB$$particle$$ooai:infoscience.tind.io:199906
000199906 937__ $$aEPFL-ARTICLE-199906
000199906 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000199906 980__ $$aARTICLE