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Abstract
Annexin A5 (ANXA5) is a member of the annexin protein family. Previous studies have shown that ANXA5 is involved in anti-inflammation and cell death. However, the detailed mechanism of the role of ANXA5 in cancer cells is not well understood. In this study, we investigated the inhibitory effect of ANXA5 on cyclooxygenase-2 (COX-2) in prostate cancer cells. Expression of COX-2 induced by TNF-α was inhibited by overexpression of ANXA5 and inhibition of COX-2 expression by auranofin, which could induce ANXA5 expression, was restored by ANXA5 knockdown. In addition, ANXA5 knockdown induces phosphorylation of NF-κB p65 in prostate cancer cells, indicating that ANXA5 causes COX-2 downregulation through inhibition of p65 activation. We also found that protein kinase C (PKC)-ζ protein levels were upregulated by the inhibition of ANXA5, although the mRNA levels were unaffected. We have shown that upregulated COX-2 expression by inhibition of ANXA5 is attenuated by PKC-ζ siRNA. In summary, this study demonstrates that downregulation of PKC-ζ-NF-κB signaling by ANXA5 may inhibit COX-2 expression in prostate cancer.
Highlights
There is increasing evidence that annexin A5 (ANXA5) has roles in cytotoxicity [1, 2], apoptosis [3, 4], and anti-inflammatory effects [5]
We have shown that upregulated cyclooxygenase 2 (COX-2) expression by inhibition of Annexin A5 (ANXA5) is attenuated by protein kinase C (PKC)-ζ siRNA
After treatment with auranofin (0.25, 0.5, or 1 μM) for 24 h, COX-2 levels were measured by quantitative PCR and western blot (Figure 1A and 1B)
Summary
There is increasing evidence that annexin A5 (ANXA5) has roles in cytotoxicity [1, 2], apoptosis [3, 4], and anti-inflammatory effects [5]. The detailed molecular mechanisms of ANXA5 in cancer cells are not yet fully understood. We found that auranofin induces expression of ANXA5 in human prostate cancer cells and triggers apoptosis [3]. Auranofin is a well-known lipophilic gold compound that has anti-inflammatory effects and immunosuppressive properties. A number of studies showed that auranofin inhibits production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase-2 (COX2) expression [6,7,8]. The repressive effect of COX-2 has been previously emphasized [9, 10]
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