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.
Highlights
Mitochondria are essential cellular organelles because of their crucial roles in cellular metabolism and respiration [1,2,3]
Mitochondrial fusion is controlled by mitofusins 1 and 2 (MFN1/2) and optic atrophy 1 (OPA1), whereas fission is driven by dynamin-related protein 1 (DRP1) [12, 13]
We show that the potent anti-leukemic effect of differentiation-inducing factor 3 (DIF-3) observed in vitro and in vivo involves impaired mitochondrial function
Summary
Mitochondria are essential cellular organelles because of their crucial roles in cellular metabolism and respiration [1,2,3]. Mitochondrial fusion and fission processes are orchestrated through the opposite actions of the family of large GTPase dynamin proteins [11]. Mitochondrial fusion is controlled by mitofusins 1 and 2 (MFN1/2) and optic atrophy 1 (OPA1), whereas fission is driven by dynamin-related protein 1 (DRP1) [12, 13]. Phosphorylation of DRP1 at Ser637 by cyclic AMP-dependent protein kinase (PKA) impairs DRP1 translocation to the mitochondria [15], whereas calcineurin-dependent dephosphorylation of the same residue enhances its recruitment to the mitochondria [16]. Phosphorylation of DRP1 at Ser616 by cyclin-dependent kinase-1 (CDK1) during mitosis promotes mitochondrial fission [17]
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