Regulation of Bcl2 Expression by the PI3KPTENAkt Pathway PCA Cells

Next, it was determined whether there is a causal relationship between activation of the PI3K/Akt pathway and upregulation of Bcl-2. A number of studies have reported either loss of PTEN or overexpression of Bcl-2 in advanced prostate tumors. However, no study has examined expression of both proteins in the same tumors. Therefore, we utilized immunohistochemistry to measure expression of PTEN and Bcl-2 in 17 cases of high-grade (Gleason score 7 or higher) prostate tumors. The findings indicate an inverse correlation of PTEN and Bcl-2 staining in 82.4% of the tumors examined (41.2% exhibited negative staining for PTEN but positive staining for Bcl-2, whereas 41.2% exhibited positive staining for PTEN but negative staining for Bcl-2). Examples of each type of staining pattern can be seen in Figure 3, where case A exhibits PTEN (+) and Bcl-2 (-), and case B exhibits PTEN (-) and Bcl-2 (+). Taken together, these studies show that Bcl-2 expression is inversely correlated with PTEN loss in many malignant prostate tissues and cell lines.

Ectopic expression of PTEN in PTEN-null cells suppresses Bcl-2 expression. Although LNCaP and PC-3 cells lack PTEN protein, both cell lines display an intact PTEN signaling pathway (18, 47-49). To determine a causal relationship between the PTEN loss and Bcl-2 overexpression, a PTEN expression vector was transiently transfected into LNCaP and PC-3 cells. As shown in Figure

4, ectopic expression of PTEN in both LNCaP and PC-3 cells resulted in decreased levels of Bcl-2 protein in a dose-dependent manner. In contrast, PTEN did not affect the expression of Bcl-XL, another anti-apoptotic member of the Bcl-2 family, in either LNCaP or PC-3 cells (Figure 4).

Further analyses indicate that PTEN down regulates Bcl-2 expression by decreasing the Akt-depedent phosphorylation of CREB, thereby modulating its transcriptional activity (21).

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