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Blood, 15 December 2001, Vol. 98, No. 13, pp. 3770-3777
NEOPLASIA
Role of protein kinase C  isoform in Fas resistance of
immature myeloid KG1a leukemic cells
Aurélie de Thonel,
Ali Bettaïeb,
Christine Jean,
Guy Laurent, and
Anne Quillet-Mary
From INSERM E9910, Institut Claudius Regaud, Toulouse;
and INSERM U517/EPHE, Faculté de Pharmacie, Dijon, France.
Leukemic CD34+ immature acute myeloid leukemia (AML)
cells express Fas receptor but are frequently resistant to Fas
agonistic reagents. Fas plays an important role in T-cell-mediated
cytotoxicity, and recently it has been suggested that altered Fas
signaling may contribute to drug resistance. Therefore, Fas resistance
could be one of the mechanisms by which AML progenitors escape
chemotherapy or T-cell-based immune intervention. However, the
molecular mechanism of Fas resistance in AML cells has not been
identified. Fas signaling can be interrupted at 3 mains levels: Fas
clustering, alteration of death-inducing-signaling-complex (DISC)
formation, and effector caspase inhibition of downstream
caspase-8. This study shows that in the Fas-resistant
CD34+CD38 KG1a cells, Fas agonists resulted
in Fas aggregation but not in caspase-8 activation, related to a defect
in DISC formation. However, pretreatment with chelerythrin, but not
with calphostin C, resulted in the restoration of Fas-induced caspase-8
activation and cytotoxicity, suggesting that some atypical protein
kinase C (PKC) isoforms contributed to the lack of DISC formation.
Indeed, treatment with antisense oligonucleotides directed against
PKC and enforced expression of Par-4, a negative regulator of PKC activity, restored Fas-induced caspase-8 activity and apoptosis. Moreover, it was found that PKC interacts with FADD and that PKC
immunoextracts prepared from KG1a cells are able to phosphorylate FADD
in vitro, whereas this phosphorylation is dramatically reduced in Par-4
transfectant cells. In conclusion, it is suggested that in AML cells,
PKC plays an important role in Fas resistance by inhibiting DISC
formation, possibly by phosphorylating FADD.
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