Upregulation of GADD153 expression in the apoptotic signaling of N‐(4‐hydroxyphenyl)retinamide (4HPR)

Induction of reactive oxygen species renders mutant and wild-type K-ras pancreatic carcinoma cells susceptible to Ad.mda-7-induced apoptosis

“…In a similar manner, induction of apoptosis by a high dose of ARS (6.25 mM) in MIA PaCa-2 and PANC-1 pancreatic cancer cells results in similar changes, including decreased Bcl-2 and increased Bax expression, cell cycle arrest in the G 2 /M phase and markedly enhanced GADD45 and GADD153 expression (Li et al, 2003). Correspondingly, treatment of specific cancers with HPR also decreases bcl-2 expression and induces or increases the levels of GADD45 and GADD153 (Delia et al, 1995;Kim et al, 2002;Xia et al, 2002;Zou et al, 2002). In these contexts, the synergy observed between the ROS-inducers and mda-7/IL-24 culminating in apoptosis in pancreatic cancer cells may proceed by inducing parallel downstream changes that normally lead to mitochondrial-mediated cell death when mda-7/ IL-24 is administered to permissive cancer cells or when the ROS-inducers are used at high concentrations.…”

“…Mechanistic studies indicate that ROS induction is a prerequisite for proapoptotic activity and emphasize the importance of the intrinsic (mitochondrial) apoptosis pathway in mediating cell killing (Jing et al, 1999;Hail and Lotan, 2000;Wu et al, 2001;Miller et al, 2002;Simeone et al, 2002;Vuky et al, 2002;Li et al, 2003). These investigations and a number of others document several interesting parallels between how ROS inducers and mda-7/IL-24 kills various tumor cells, including pancreatic tumor cells following ablation of K-ras (Su et al, 2001) or treatment with ARS, HPR or NSC (Delia et al, 1995;Jing et al, 1999;Hail and Lotan, 2000;Wu et al, 2001;Kim et al, 2002;Miller et al, 2002;Simeone et al, 2002;Vuky et al, 2002;Xia et al, 2002;Zou et al, 2002;Lebedeva et al, 2003b;Li et al, 2003). Apoptosis induced by Ad.mda-7 in 'permissive' prostate, melanoma and malignant glioma cells and in 'resistant' pancreatic cancer cells (simultaneously treated with K-ras antisense phosphorothioate oligonucleotides) results in alterations in the ratio of antiapoptotic (such as Bcl-2 and Bcl-x L ) and proapoptotic (including Bax and Bak) proteins, changes in cell cycle resulting in accumulation of cells in the G 2 /M phase and upregulation in expression of the growth arrest and DNA damage inducible (GADD) gene family (Su et al, 2001Lebedeva et al, 2002Lebedeva et al, , 2003aSarkar et al, 2002b).…”

Modulation of death receptors by cancer therapeutic agents

“…97 Several studies have shown that 4HPR and its analog induce CHOP expression in different types of cancer cells, which plays a role in 4HPR-induced apoptosis. [98][99][100][101][102][103] Therefore, these data suggest that 4HPR induces CHOP-dependent DR5 expression.…”

Green tea polyphenol stimulates cancer preventive effects of celecoxib in human lung cancer cells by upregulation of GADD153 gene

“…10 Furthermore, it has been reported that GADD153 protein plays an important role in the induction of apoptosis of cancer cells treated with N-(4-hydroxyphenyl)retinamide (4HPR), a synthetic retinoid, as a retinoic acid receptor-independent pathway. 11,12 In addition to 4HPR, various cancer preventive agents-such as curcumin, thiazolidinedione (an agonist of peroxisome proliferator-activated receptor-g) and phenethylisothiocyanate-induced apoptosis of cancer cells mediated through upregulation of GADD153 gene. [13][14][15] These results strongly suggest that overexpression of GADD153 gene is a new molecular mechanism of antitumor activity by cancer preventive agents.…”