Background and purpose: 3-phosphoinositide-dependent kinase-1 (PDK1) plays vital role in cell growth

proliferation and survival. Dysfunctional PDK1 involves in various carcinogenesis. This study aimed to determine the abundance of PDK1 in chronic myelogenous leukemia (CML) cells and study the molecular basis of its contribution to anti-apoptotic phenotype. Methods: The expression of protein was detected by Western blot. Flow cytometry was conducted to analyze the apoptotic cells. Clone formation assay and cell counting kit-8 (CCK-8) were employed to examine the inhibition of proliferation. Results: In comparison with heathy donors

PDK1 in CML cells was significantly over-expressed (P0.05). In K562 and KU812 cell lines

blockage of PDK1 resulted in remarkable reduction of growth and induction of apoptosis (P0.01)

which was further validated by cleavage of the caspase-3 and its substrate poly (ADP-ribose) polymerase (PARP). The PDK1 inhibitor

GSK2334470 lowered the phosphorylation

but not the total PDK1 level (in K562 cells

P0.05; in KU812 cells

P0.01). Besides

the decrease in protein kinase B (AKT) and downstream glycogen synthase kinase-3β (GSK-3β) phosphorylation was also found in two cell lines. However

no significant change of β-catenin was detected

consequently

no effect was found on the expression of c-Myc

the targeted gene of this pathway (P0.05). Moreover

PDK1 inhibition caused evident decrease in apoptosis signal-regulating kinase 1 (ASK1) phosphorylation (P0.001)

which further led to activation of c-Jun N-terminal kinase (JNK) and Bcl-2 interacting mediator of cell death (Bim). Finally

GSK2334470 enhanced the sensitivity of imatinib (P0.01). Conclusion: PDK1 inhibition triggered cell death by modulation of ASK1/JNK/Bim cascade.