Oncotarget

Research Papers:

Differentiation inducing factor 3 mediates its anti-leukemic effect through ROS-dependent DRP1-mediated mitochondrial fission and induction of caspase-independent cell death

Alix Dubois _, Clemence Ginet, Nathan Furstoss, Amine Belaid, Mohamed Amine Hamouda, Wedjene El Manaa, Thomas Cluzeau, Sandrine Marchetti, Jean Ehrland Ricci, Arnaud Jacquel, Frederic Luciano, Mohsine Driowya, Rachid Benhida, Patrick Auberger and Guillaume Robert

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Oncotarget. 2016; 7:26120-26136. https://doi.org/10.18632/oncotarget.8319

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Abstract

Alix Dubois1,2,3,4, Clemence Ginet1,2,3,4, Nathan Furstoss1,2,3,4, Amine Belaid1,2,4, Mohamed Amine Hamouda1,2,3,4, Wedjene El Manaa1,2,3,4, Thomas Cluzeau1,2,3,4,5,6, Sandrine Marchetti1,2,3,4, Jean Ehrland Ricci1,4,7, Arnaud Jacquel1,2,3,4, Frederic Luciano1,2,3,4, Mohsine Driowya4,5, Rachid Benhida4,5, Patrick Auberger1,2,3,4,6,*, Guillaume Robert1,2,3,4,*

1INSERM U1065 Centre Méditerranéen de Médecine Moléculaire, Nice, France

2Team 2: Cell Death, Differentiation, Inflammation and Cancer, Nice, France

3Equipe Labellisée Fondation ARC, Paris, France

4Université de Nice Sophia Antipolis, Nice, France

5Institut de Chimie de Nice (ICN), UMR 7272, Nice, France

6CHU de Nice, Service d’Hématologie Clinique, Nice, France

7Team 3: Regulation of Caspase Dependent and Independent Cell Death, Nice, France

*The last two authors have contributed equally to this work

Correspondence to:

Guillaume Robert, e-mail: [email protected]

Keywords: DIF-3, mitochondria fission, cell death, autophagy, leukemia

Received: September 29, 2015     Accepted: March 08, 2016     Published: March 24, 2016

ABSTRACT

Differentiation-inducing factor (DIF) defines a group of chlorinated hexaphenones that orchestrate stalk-cell differentiation in the slime mold Dictyostelium discoideum (DD). DIF-1 and 3 have also been reported to have tumor inhibiting properties; however, the mechanisms that underlie the effects of these compounds remain poorly defined. Herein, we show that DIF-3 rapidly triggers Ca2+ release and a loss of mitochondrial membrane potential (MMP) in the absence of cytochrome c and Smac release and without caspase activation. Consistently with these findings, we also detected no evidence of apoptosis in cells treated with DIF-3 but instead found that this compound induced autophagy. In addition, DIF-3 promoted mitochondrial fission in K562 and HeLa cells, as assessed by electron and confocal microscopy analysis. Importantly, DIF-3 mediated the phosphorylation and redistribution of dynamin-related protein 1 (DRP1) from the cytoplasmic to the microsomal fraction of K562 cells. Pharmacological inhibition or siRNA silencing of DRP1 not only inhibited mitochondrial fission but also protected K562 cells from DIF-3-mediated cell death. Furthermore, DIF-3 potently inhibited the growth of imatinib-sensitive and imatinib-resistant K562 cells. It also inhibited tumor formation in athymic mice engrafted with an imatinib-resistant CML cell line. Finally, DIF-3 exhibited a clear selectivity toward CD34+ leukemic cells from CML patients, compared with CD34- cells. In conclusion, we show that the potent anti-leukemic effect of DIF-3 is mediated through the induction of mitochondrial fission and caspase-independent cell death. Our findings may have important therapeutic implications, especially in the treatment of tumors that exhibit defects in apoptosis regulation.


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