CAAT/Enhancer Binding Protein Homologous Protein–Dependent Death Receptor 5 Induction Is a Major Component of SHetA2-Induced Apoptosis in Lung Cancer Cells

Abstract

The flexible heteroarotinoids (Flex-Het) represent a novel type of atypical retinoids lacking activity in binding to and transactivating retinoid receptors. Preclinical studies have shown that Flex-Hets induce apoptosis of cancer cells while sparing normal cells and exhibit anticancer activity in vivo with improved therapeutic ratios over conventional retinoid receptor agonists. Flex-Hets have been shown to induce apoptosis through activation of the intrinsic apoptotic pathway. The present study has revealed a novel mechanism underlying Flex-Het-induced apoptosis involving induction of death receptor 5 (DR5). The representative Flex-Het SHetA2 effectively inhibited the growth of human lung cancer cells in cell culture and in mice. SHetA2 induced apoptosis, which could be abrogated by silencing caspase-8 expression, indicating that ShetA2 triggers a caspase-8-dependent apoptosis. Accordingly, SHetA2 up-regulated DR5 expression, including cell surface levels of DR5, and augmented tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Importantly, small interfering RNA (siRNA)-mediated blockade of DR5 induction conferred cell resistance to SHetA2-induced apoptosis, as well as SHetA2/TRAIL-induced apoptosis. These results show that DR5 induction is a key component of apoptosis induced by SHetA2 or by SHetA2 combined with TRAIL. SHetA2 exerted CAAT/enhancerbinding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter. Consistently, SHetA2 induced CHOP expression, which paralleled DR5 up-regulation, whereas siRNA-mediated blockage of CHOP induction prevented DR5 up-regulation, indicating CHOP-dependent DR5 up-regulation by SHetA2. Collectively, we conclude that CHOP-dependent DR5 up-regulation is a key event mediating SHetA2-induced apoptosis. [Cancer Res 2008;68(13):5335-44]

Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

“…HEK-293T cells were provided by K. Ye (Emory University, Atlanta, GA). The human lung cancer cell lines A549, H1792, H157, and Calu-1 were described previously (24). The rest of the cancer cell lines were provided by Dr. P. Giannakakou (Weill Medical College of Cornell University, New York, NY).…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Elevated expression of CHOP is observed in tumors after chemotherapy or as a consequence of uncontrolled growth of malignant cells (Schonthal 2013;Flaherty et al 2014). Upon drug treatment, CHOP induction enhances apoptosis through transactivation of DR5 in human carcinoma (Yamaguchi and Wang 2004), prostate cancer (Shiraishi et al 2005), pancreatic cancer (Abdelrahim et al 2006), and lung cancer (Lin et al 2008). CHOP also inhibits the expression of transferrin, a key protein for cell survival in hepatoma cells, decreasing tumor cell viability (You et al 2003).…”

Involvement of c-FLIP and survivin down-regulation in flexible heteroarotinoid-induced apoptosis and enhancement of TRAIL-initiated apoptosis in lung cancer cells

“…We have shown recently that SHetA2 effectively inhibits the growth and induces apoptosis of human non-small cell lung cancer (NSCLC; ref. 32). Moreover, SHetA2 cooperates with the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to augment induction of apoptosis (32).…”

“…32). Moreover, SHetA2 cooperates with the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to augment induction of apoptosis (32). These effects are tightly associated with death receptor 5 (DR5) up-regulation (32), implying the importance of activation of the extrinsic apoptotic pathway in SHetA2-induced apoptosis.…”