Co-existence of high levels of the PTEN protein with enhanced Akt activation in renal cell carcinoma.
Recruiting Akt to the membrane-bound phosphatidylinositol (3,4,5) trisphosphate (PIP3) is required for Akt activation. While PI3 kinase (PI3K) produces PIP3, PTEN dephosphorylates the 3-position phosphate from PIP3, thereby directly inhibiting Akt activation. PTEN is the dominant PIP3 phosphatase, as knockdown of PTEN results in increases in Akt activation in mice. The PTEN tumor suppressor gene is frequently mutated in a variety of human cancers, consistent with an inverse correlation between levels of the PTEN protein and Akt activation. We have examined PTEN expression and Akt activation in 35 primary clear cell renal cell carcinomas RCCs (ccRCCs) and 9 papillary RCCs (pRCCs) and their respective non-tumor kidney tissues. The PTEN protein was reduced in 16 ccRCCs (16/35=45.7%) and 8 pRCCs (8/9=88.9%). In these RCCs, 25.0% (4/16) of ccRCCs and 25.0% (2/8) of pRCCs expressed elevated Akt activation. 19 ccRCCc (19/35=54.3%) expressed comparable or higher levels of PTEN. Of these ccRCCs, 31.6% (6/19) showed increases in Akt activation. As PTEN dominantly inhibits Akt activation, the coexistence of high levels of the PTEN protein with enhanced Akt activation suggests the existence of novel mechanisms which attenuate PTEN function in ccRCC. These mechanisms may reduce PTEN function or increase PIP3 production.
Division of Nephrology, Department of Medicine, McMaster University, and Father Sean O'Sullivan Research Centre, St. Joseph's Hospital, 50 Charlton Ave East, Hamilton, ON, Canada L8N 4A6.
Lizhi
L
He
Catherine
C
Fan
Aubrey
A
Gillis
Xinchang
X
Feng
Michael
M
Sanatani
Sebastien
S
Hotte
Anil
A
Kapoor
Damu
D
Tang
D000818:Animals; D002291:Carcinoma, Papillary / Q000201:enzymology* / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D018129:Phosphatidylinositol Phosphates; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse