Abstract
The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. Among different structurally related COX-2 inhibitors, only celecoxib was found to cause apoptosis and cell death of human lung cancer cells (IC₅₀ values of 19.96 µM [A549], 12.48 µM [H460], and 41.39 µM [H358]) that was paralleled by a time- and concentration-dependent upregulation of COX-2 and peroxisome proliferator-activated receptor γ (PPARγ) at mRNA and protein levels. Apoptotic death of celecoxib-treated cancer cells was suppressed by the PPARγ antagonist GW9662 and by siRNA targeting PPARγ and, surprisingly, also by the selective COX-2 inhibitor NS-398 and siRNA targeting COX-2. NS-398 (1 µM) was shown to suppress celecoxib-induced COX-2 activity. Among the COX-2-dependent prostaglandins (PG) induced upon celecoxib treatment, PGD₂ and 15-deoxy-Δ¹²,¹⁴-PGJ₂ were found to induce a cytosol-to-nucleus translocation of PPARγ as well as a PPARγ-dependent apoptosis. Celecoxib-elicited PPARγ translocation was inhibited by NS-398. Finally, a COX-2- and PPARγ-dependent cytotoxic action of celecoxib was proven for primary human lung tumor cells. Together, our data demonstrate a proapoptotic mechanism of celecoxib involving initial upregulation of COX-2 and PPARγ and a subsequent nuclear translocation of PPARγ by COX-2-dependent PGs.
Highlights
The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate
The impact of celecoxib on COX-2 and PPAR␥ expression was assessed in A549, H460, and H358, as well as in primary tumor cells obtained from resections of brain metastases of two non-small cell lung cancer (NSCLC) patients
The present study demonstrates induction of COX-2 expression followed by activation of PPAR␥ as key events within the proapoptotic action of the selective COX-2 inhibitor celecoxib on human lung cancer cells
Summary
The antitumorigenic mechanism of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib is still a matter of debate. In addition and in contrast to the traditional view implying a protumorigenic function of COX-2 [19, 20], overexpression of COX-2 decreased proliferation and increased apoptosis of osteosarcoma cells [21], and it protected rather than sensitized animals to experimental skin tumor development [22] In line with these findings, COX-2 upregulation has emerged as a proapoptotic mechanism shared by various antitumorigenic compounds [23,24,25,26,27,28,29,30]. Regarding the mechanism underlying COX-2-dependent apoptosis, several studies indicated that COX-2-derived PGD2 and 15-deoxy-⌬12,14-PGJ2 (15d-PGJ2) confer this response by activating the transcription factor peroxisome proliferator activated receptor ␥ (PPAR␥) [27, 28, 31,32,33], which has proved as an attractive anticancer target in recent years [34,35,36].
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