Data from 15d-PGJ₂ Induces Apoptosis by Reactive Oxygen Species–mediated Inactivation of Akt in Leukemia and Colorectal Cancer Cells and Shows <i>In vivo</i> Antitumor Activity

Abstract

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Recent studies have shown that 15-deoxy-Δ&lt;sup&gt;12, 14&lt;/sup&gt;-prostaglandin J&lt;sub&gt;2&lt;/sub&gt; (15d-PGJ&lt;sub&gt;2&lt;/sub&gt;), a natural ligand for peroxisome proliferator–activated receptor-γ (PPARγ), inhibits cell proliferation and induces apoptosis. The specific molecular mechanisms underlying this effect remain to be elucidated. We examined whether 15d-PGJ&lt;sub&gt;2&lt;/sub&gt; has antitumor activity &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;, and investigated the underlying mechanism.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; We examined 15d-PGJ&lt;sub&gt;2&lt;/sub&gt;–induced apoptosis in human leukemia cells in the context of mitochondrial injury, oxidative damage, and signaling pathway disturbances. In addition, we investigated the antitumor effect of 15d-PGJ&lt;sub&gt;2&lt;/sub&gt; in a mouse CT-26 s.c. tumor model and HL-60 leukemia xenograft model.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; 15d-PGJ&lt;sub&gt;2&lt;/sub&gt; induced apoptosis in leukemia and colorectal cancer cells in a dose-dependent manner and led to generation of reactive oxygen species (ROS) through mitochondria and NADPH oxidase activation, activation of JNK, and inactivation of Akt, a serine/threonine-specific protein kinase. Constitutive activation of Akt for an engineered myristoylated protein prevented 15d-PGJ&lt;sub&gt;2&lt;/sub&gt;–mediated apoptosis but not ROS generation. Collectively, these findings suggest a hierarchical model of apoptosis induced by 15d-PGJ&lt;sub&gt;2&lt;/sub&gt; in human leukemia cells: oxidative injury represents a primary event resulting in Akt inactivation, which in turn leads to mitochondrial injury and apoptosis. Moreover, 15d-PGJ&lt;sub&gt;2&lt;/sub&gt; markedly reduced growth of mouse CT-26 s.c. tumors and HL-60 xenograft tumors and down-regulated p-Akt and Akt expression &lt;i&gt;in vivo&lt;/i&gt;.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; These results suggest that Akt inactivation through ROS production may contribute to 15d-PGJ&lt;sub&gt;2&lt;/sub&gt;–induced apoptosis in leukemia and colorectal cancer cell lines and that 15d-PGJ&lt;sub&gt;2&lt;/sub&gt; may have therapeutic relevance in the treatment of human leukemia and colorectal cancer. (Clin Cancer Res 2009;15(17):5414–25)&lt;/p&gt;&lt;/div&gt;