当前位置： SCI文献检索 > CANCER RESEARCH期刊下所有文献 > Sensitization of mesothelioma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by heat stress via the inhibition of the 3-phosphoinositide-dependent kinase 1/Akt pathway.

Sensitization of mesothelioma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by heat stress via the inhibition of the 3-phosphoinositide-dependent kinase 1/Akt pathway.

Abstract：

:Heat stress may enhance the effect of apoptosis-inducing agents in resistant tumor cells. One such agent is the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which has attracted intense interest for its ability to induce apoptosis in tumors without affecting nonmalignant cells. We therefore tested whether heat stress potentiates TRAIL-induced apoptosis in mesothelioma cells, its cell type being resistant to TRAIL alone. We found that heat stress enhanced the apoptosis caused by TRAIL but not by chemotherapy. To explain this potentiation, we found that heat stress decreased Akt phosphorylation via the dissociation of heat shock protein 90 (Hsp90) from its client protein 3-phosphoinositide-dependent kinase 1 (PDK-1), a major Akt kinase. The role of Hsp90 and the Akt pathway was confirmed by showing that inhibitors of Hsp90 and the phosphatidyilinositol-3 kinase/Akt pathway reproduced the effect of heat stress on TRAIL-induced apoptosis and that the effect of inhibiting Hsp90 on TRAIL-induced apoptosis could be overcome by activating the Akt pathway with a constitutively active construct of the Akt kinase PDK-1. The effect of heat stress involved multiple steps of the apoptotic machinery. Heat stress potentiated the death receptor pathway, as shown by an increase in TRAIL-induced caspase 8 cleavage. Nonetheless, knockdown of Bid, the main intermediary molecule from the death receptor pathway to the mitochondria, inhibited the effect of heat stress, showing that mitochondrial amplification was required for potentiation by heat stress. In summary, these results support the novel concept that heat stress inhibits the Akt pathway by dissociating PDK-1 from its chaperone Hsp90, leading to potentiation of TRAIL-induced apoptosis in resistant malignant cells.

journal_name

Cancer Res

journal_title

Cancer research

authors

Pespeni MH,Hodnett M,Abayasiriwardana KS,Roux J,Howard M,Broaddus VC,Pittet JF

doi

10.1158/0008-5472.CAN-06-3871

subject

Has Abstract

pub_date

2007-03-15 00:00:00

pages

2865-71

issue

eissn

0008-5472

issn

1538-7445

pii

67/6/2865

journal_volume

pub_type

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Sensitization of mesothelioma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by heat stress via the inhibition of the 3-phosphoinositide-dependent kinase 1/Akt pathway.