The Cyclooxygenase-2 Inhibitor Celecoxib Induces Apoptosis by Blocking Akt Activation in Human Prostate Cancer Cells Independently of Bcl-2*
By A. Hsu, T. Ching, Dasheng Wang, Xueqin Song, V. Rangnekar, Ching-shih Chen. Journal of Biological Chemistry, 2000
706 citations recorded by the source corpus.
This study investigates the apoptotic activity of the cyclooxygenase-2 (COX-2) inhibitor celecoxib in prostate carcinoma cells. COX-2 is constitutively expressed in androgen-responsive LNCaP and androgen-nonresponsive PC-3 cells. Exposure of these cells to celecoxib induces characteristic features of apoptosis, including morphological changes, DNA laddering, and caspase-3 activation, whereas piroxicam, a COX-1-specific inhibitor, displays no appreciable effect on either cancer cell line even after prolonged exposure. Moreover, the potency of celecoxib in apoptosis induction is significantly higher than that of other COX-2 inhibitors examined despite the observation that these inhibitors exhibit similar IC50 in COX-2 inhibition. It is noteworthy that normal human prostate epithelial cells, expressing a marginally detectable level of COX-2, are insensitive to the induction of apoptosis by celecoxib. These data suggest a correlation between COX-2 expression and sensitivity to the apoptotic effect of the COX-2 inhibitor. In an effort to delineate the underlying mechanism, we examined the effect of celecoxib on the expression of Bcl-2 as well as the activation of the key anti-apoptotic kinase Akt. In contrast to an earlier report that attributed the apoptotic activity of NS398 in LNCaP cells to Bcl-2 down-regulation, we provide evidence that the induction of apoptosis by celecoxib in LNCaP and PC-3 cells is independent of Bcl-2. First, treatment with celecoxib does not alter the cellular Bcl-2 level in both cell lines. Second, enforced Bcl-2 expression in PC-3 cells does not confer protection against the induction of apoptosis by celecoxib. Our data show that celecoxib treatment blocks the phosphorylation of Akt. This correlation is supported by studies showing that overexpression of constitutively active Akt protects PC-3 cells from celecoxib-induced apoptosis. Nevertheless, how celecoxib down-regulates Akt is not clear because the drug does not adversely affect phosphoinositide 3-kinase activity in vivo and okadaic acid, a protein phosphatase 2A inhibitor, cannot rescue the inhibition. In summary, our data demonstrate that inhibition of Akt activation may play a crucial role in the induction of apoptosis by celecoxib.
Subfields: Biochemistry, Genetics, Pharmacology
View Paper: https://www.semanticscholar.org/paper/9a16844e3252f3ad809cb33cd5f7e9c8a0f29272
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Citations in the corpus
- Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. (2008, background): “The selective COX-2 inhibitor celecoxib induces apoptosis in human prostate cancer cell lines (PC-3) expressing COX-2 by blocking antiapoptotic kinase Akt activation, and the antiangiogenic activity of COX-2 inhibitors may constitute another mechanism to prevent tumor growth (65, 66).”
- Cyclooxygenase‐independent actions of cyclooxygenase inhibitors (2001, background): “Celecoxib was recently shown to induce apoptosis in COX-2-expressing, androgen-responsive (LNCaP) and nonresponsive (PC-3) prostate cancer cells (208).”
- Vascular Endothelial Growth Factor and Angiogenesis (2004, background): “Celecoxib, a potent and selective COX-2 inhibitor, induces apoptosis by blocking Akt activation (Hsu et al., 2000).”
- Cyclo‐Oxygenase 2 Function Is Essential for Bone Fracture Healing (2002, background): “Such an effect on chondrocytes could occur through a direct effect on differentiation or indirectly by preventing premature apoptosis because inhibition of COX-2 function by COX2–selective NSAIDs has been shown to induce apoptosis in cancer cell lines.((42)) The potential effects of prostaglandins o”