Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3β activity in human breast cancer cells

Abstract

Prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosene) is a bacterial metabolite that has anticancer and antimetastatic properties. However, the molecular mechanisms responsible for these abilities are not fully understood. Gene expression profiling of the human breast cancer cell line MCF-7 treated with prodigiosin was analyzed by cDNA array technology. The majority of the significantly modified genes were related to apoptosis, cell cycle, cellular adhesion, or transcription regulation. The dramatic increase of the nonsteroidal anti-inflammatory drugactivated gene 1 (NAG-1) made this gene an interesting candidate regarding the possible mechanism by which prodigiosin induces cytotoxicity in MCF-7 cells. Our results show that prodigiosin triggers accumulation of the DNAdamage response tumor-suppressor protein p53 but that NAG-1 induction was independent of p53 accumulation. Moreover, prodigiosin caused AKT dephosphorylation and glycogen synthase kinase-3B (GSK-3B) activation, which correlated with NAG-1 expression. Prodigiosin-induced apoptosis was recovered by inhibiting GSK-3B, which might be due, at least in part, to the blockade of the GSK-3B -dependent up-regulation of death receptors 4 and 5 expression. These findings suggest that prodigiosinmediated GSK-3B activation is a key event in regulating the molecular pathways that trigger the apoptosis induced by this anticancer agent. [Mol Cancer Ther 2007;6(1):362 -9]

A novel anticancer effect of Astragalus saponins: Transcriptional activation of NSAID‐activated gene

“…The reason why we were interested in studying NAG-1 as a molecular drug target was because of the previous reports that anticancer drugs could induce apoptosis by causing Akt dephosphorylation and glycogen synthase kinase (GSK) 3b activation, which eventually modulate NAG-1 upregulation-a proposed Akt/ GSK3b/NAG-1 pathway. 33,34 We had actually shown that AST treatment for 6-72 hr induces phospho-GSK3b overexpression in HT-29 cells time-dependently (Supporting Information Fig. 2), which is consistent with the upregulation of NAG-1.…”

Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells

“…Given the importance of Wnt/β-catenin signaling in the development of human cancers (1-4), the Wnt inhibitory function of prodigiosin may be attributed to its selective cytotoxicity toward cancer cells. A previous study noted that prodigiosin-induced apoptosis could be blocked by GSK3β pharmacologic inactivation, suggesting that prodigiosin may mediate GSK3β activation (17). In this study, we have demonstrated that prodigiosin can reduce GSK3β phosphorylation at Ser9, leading to the increased activity of GSK3β.…”

“…A previous study indicated that pharmacologic inhibitors of GSK3β could prevent prodigiosin toxicity (17). Thus, we evaluated the effect of prodigiosin on the phosphorylation state of GSK3β, a serine/threonine kinase involved in various cellular responses, including regulation of β-catenin stability.…”

“…The specific mechanisms of prodigiosin action in malignant cells have been poorly elucidated, however. In breast cancer cells, pharmacologic inhibitors of GSK3β have been reported to prevent prodigiosin toxicity (17). Inhibitors of GSK3β promote β-catenin-dependent Wnt pathway activation.…”

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

“…The National Cancer Institute (dtp.nci.nih.gov) tested prodigiosin (and some of its derivates) against a collection of ~ 60 cell lines with an average IC 50 (for PG) of 2.1 µM (1). It has been described that the apoptotic process triggered by PG is mediated through the mitochondrial pathway and involves the induction of the proapoptotic gene NAG-1 (2). Nevertheless, the molecular target of this agent is still unknown.…”