TY - JOUR
T1 - Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR
AU - Dutton, Amanda
AU - Reynolds, Gary M.
AU - Dawson, Christopher W.
AU - Young, Lawrence S.
AU - Murray, Paul G.
PY - 2005/3
Y1 - 2005/3
N2 - The molecular mechanisms underlying the pathogenesis of the malignant Hodgkin's/Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL) are largely unknown. This study investigates the contribution of phosphatidyl-inositide 3 kinase (PI3-kinase) and demonstrates that Akt, a substrate of PI3-kinase, is constitutively activated in HL-derived cell lines. Several downstream effectors of Akt signalling, including glycogen synthase kinase 3 (GSK-3) α and β and mTOR substrates 4E-BP1 and p70 S6 kinase, were also phosphorylated in HL cells. The mTOR inhibitor, rapamycin, inhibited phosphorylation of these proteins. Furthermore, LY294002 inhibited phosphorylation of p70 S6 kinase and 4E-BP1, suggesting that the phosphorylation of p70 S6 kinase and 4E-BP1 in HL cells is PI3-kinase dependent. Importantly, HRS cells of primary tumour samples not only expressed high levels of activated Akt but also displayed phosphorylation of downstream targets of Akt activation including GSK-3, 4E-BP1, and p70 S6 Kinase. Inhibition of PI3-kinase and mTOR showed only modest effects on cell survival at the lower serum concentrations. However, rapamycin and doxorubicin acted synergistically to reduce HL cell survival. A combination of rapamycin and chemotherapy should be investigated in the treatment of HL.
AB - The molecular mechanisms underlying the pathogenesis of the malignant Hodgkin's/Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL) are largely unknown. This study investigates the contribution of phosphatidyl-inositide 3 kinase (PI3-kinase) and demonstrates that Akt, a substrate of PI3-kinase, is constitutively activated in HL-derived cell lines. Several downstream effectors of Akt signalling, including glycogen synthase kinase 3 (GSK-3) α and β and mTOR substrates 4E-BP1 and p70 S6 kinase, were also phosphorylated in HL cells. The mTOR inhibitor, rapamycin, inhibited phosphorylation of these proteins. Furthermore, LY294002 inhibited phosphorylation of p70 S6 kinase and 4E-BP1, suggesting that the phosphorylation of p70 S6 kinase and 4E-BP1 in HL cells is PI3-kinase dependent. Importantly, HRS cells of primary tumour samples not only expressed high levels of activated Akt but also displayed phosphorylation of downstream targets of Akt activation including GSK-3, 4E-BP1, and p70 S6 Kinase. Inhibition of PI3-kinase and mTOR showed only modest effects on cell survival at the lower serum concentrations. However, rapamycin and doxorubicin acted synergistically to reduce HL cell survival. A combination of rapamycin and chemotherapy should be investigated in the treatment of HL.
KW - Hodgkin's lymphoma
KW - mTOR
KW - pAkt
KW - PI3-kinase
UR - http://www.scopus.com/inward/record.url?scp=14944339657&partnerID=8YFLogxK
U2 - 10.1002/path.1725
DO - 10.1002/path.1725
M3 - Article
C2 - 15714459
AN - SCOPUS:14944339657
SN - 0022-3417
VL - 205
SP - 498
EP - 506
JO - The Journal of Pathology
JF - The Journal of Pathology
IS - 4
ER -