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Differentiation Inducing Factor 3 Mediates Its Anti-Leukemic Effect Through ROS-dependent DRP1-mediated Mitochondrial Fission and Induction of Caspase-Independent Cell Death

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, etc.

Oncotarget. 2016 May 3;7(18):26120-36.

PMID: 27027430

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP113411179	DIF-3		113411-17-9	Price

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