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Phosphatidylinositol-3 kinase (PI3K)/Akt inhibition promoted apoptosis in Hodgkin lymphoma (HL)

07-21-2006

"Activation of the PI3K pathway has been linked with tumor cell growth, survival and resistance to therapy in several cancer types. The active, phosphorylated form of Akt (pAkt) was found to be aberrantly expressed in HL-derived cell lines and in Hodgkin-Reed-Sternberg (HRS) cells in 27 of 42 (64.3%) of primary lymph node sections of HL, indicative of PI3K activity," investigators in the United States reported.

"Akt phosphorylation was not associated with loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression, but with its phosphorylation in HL-cell lines, suggesting that its biological function is impaired. Akt phosphorylation was further induced by CD30 ligand (CD30L), CD40L and receptor activator of nuclear factor kappa B (RANK) ligand," explained G.V. Georgakis and colleagues, M.D. Anderson Cancer Center.

"The PI3K inhibitor LY294002 demonstrated antiproliferative effects in a dose- and time-dependent manner, which was associated with Akt dephosphorylation on Thr-308 and Ser-473 sites and dephosphorylation of the downstream ribosomal protein S6."

"LY209002 induced cell cycle arrest in the G0/G1 phase and apoptosis, which were associated with upregulation of MDM2, downregulation of cyclin D1, activation of caspase 9 and poly-ADP-ribose polymerase cleavage. The Akt inhibitor QLT394 also demonstrated antiproliferative effects in a dose- and time-dependent manner, dephosphorylated ribosomal S6 and cleaved caspase 9. Collectively, these data suggest that the aberrant activation of the PI3K/Akt survival pathway in HRS cells is not because of loss of PTEN expression."

The researchers concluded, "Our data suggest that PTEN phosphorylation and activation of CD30, CD40 and RANK may play a role in activating Akt in HRS cells."

Georgakis and colleagues published their study in British Journal of Haematology (Inhibition of the phosphatidylinositol-3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma. Br J Haematol, 2006;132(4):503-511).

For additional information, contact A. Younes, M.D. Anderson Cancer Center, Dept. Lymphoma Myeloma, 1515 Holcombe Blvd., Houston, TX 77030, USA.

The publisher of the British Journal of Haematology can be contacted at: Blackwell Publishing, 9600 Garsington Rd., Oxford OX4 2DQ, Oxon, England.

This article was prepared by Cancer Gene Therapy Week editors from staff and other reports. Copyright 2006, Cancer Gene Therapy Week via NewsRx.com.