[Recent anti-aging studies on caloric restriction and resveratrol].

Seventy-five years after its initial report, lifespan prolongation by caloric restriction (CR) has been confirmed in many animal species. Gathered evidences suggest that the histone deacetylase Sir2/SIRT1 is a key mediator. Moreover, resveratrol (RSV), a plant derived polyphenol, was shown to increase SIRT1 catalytic activity and mimics many aspects of CR in all eukaryotes tested. Therefore, RSV displays great promise in the prevention of illness and delay the aging process.

Bombesin enhances TGF-beta growth inhibitory effect through apoptosis induction in intestinal epithelial cells.

Mammalian intestinal epithelium undergoes continuous cell turn over, with cell proliferation in the crypts and apoptosis in the villus. Both transforming growth factor (TGF)-beta and gastrin-releasing peptide (GRP) are involved in the regulation of intestinal epithelial cells for division, differentiation, adhesion, migration and death. Previously, we have shown that TGF-beta and bombesin (BBS) synergistically induce cyclooxygenase-2 (COX-2) expression and subsequent prostaglandin E(2) (PGE2) production through p38(MAPK) in rat intestinal epithelial cell line stably transfected with GRP receptor (RIE/GRPR), suggesting the interaction between TGF-beta signaling pathway and GRPR. The current study examined the biological responses of RIE/GRPR cells to TGF-beta and BBS. Treatment with TGF-beta1 (40 pM) and BBS (100 nM) together synergistically inhibited RIE/GRPR growth and induced apoptosis. Pretreatment with SB203580 (10 microM), a specific inhibitor of p38(MAPK), partially blocked the synergistic effect of TGF-beta and BBS on apoptosis. In conclusion, BBS enhanced TGF-beta growth inhibitory effect through apoptosis induction, which is at least partially mediated by p38(MAPK).

Synergistic regulation of COX-2 expression by bombesin and transforming growth factor-beta.

Overexpression of cyclooxygenase-2 (COX-2), an inducible enzyme regulating prostaglandin release, is mechanistically linked to the development, growth, and spread of gastrointestinal (GI) cancers. GI peptide bombesin (BBS) was reported to stimulate COX-2 gene expression. Here we show that TGF-beta1 dramatically enhances the BBS-induced expression of COX-2 mRNA and protein, and the release of PGE2 in the model rat intestinal epithelial cell (RIE-1) line. The synergistic increase in COX-2 levels results from a combination of enhanced COX-2 transcription and reduced mRNA degradation. BBS, but not TGF-beta1, stimulated COX-2 promoter activity, and TGF-beta1 enhanced COX-2 mRNA stability through a p38(MAPK)-dependent pathway. The synergistic regulation of COX-2 expression by TGF-beta1 and BBS may contribute to the upregulation of COX-2 in GI cancers.

Bombesin stimulates nuclear factor kappa B activation and expression of proangiogenic factors in prostate cancer cells.

The majority of deaths from prostate cancer occur in patients with androgen-insensitive metastatic disease. An important early event in the development of the metastatic phenotype is the induction of genes that promote angiogenesis, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), which are released from tumor cells into their microenvironment. Coincident with progression from prostatic carcinoma in situ to metastatic disease is an increase in the number of tumor cells exhibiting neuroendocrine (NE) differentiation. NE cells express a variety of peptide hormones, including the bombesin (BBS)-like peptide, gastrin-releasing peptide (GRP), and its cognate receptor, GRP-R. Although there is a strong positive correlation between the degree of NE differentiation and the metastatic potential of prostate cancers, a mechanistic link between increased expression of peptide hormone receptors, such as GRP-R, and proangiogenic gene expression has not been established. Here we report that BBS stimulates nuclear factor kappa B (NF kappa B) activation and proangiogenic gene expression in the androgen-insensitive prostate cancer cells lines, PC-3 and DU-145. In PC-3 cells, BBS stimulation of GRP-R resulted in the up-regulation of IL-8 and VEGF expression through a NF kappa B-dependent pathway. We show that BBS treatment induced inhibitor of NF kappa B degradation, NF kappa B translocation to the cell nucleus, increased NF kappa B binding to its DNA consensus sequence, and increased IL-8 and VEGF mRNA expression and protein secretion. Treatment with the proteasome inhibitor, MG-132, blocked BBS-stimulated NF kappa B DNA binding, and IL-8 and VEGF expression and secretion. Finally, media collected from PC-3 cell cultures, after BBS treatment, stimulated an NF kappa B-dependent migration of human umbilical vascular endothelial cells in vitro. Together, our data demonstrate a role for BBS and GRP-R in the NF kappa B-dependent up-regulation of proangiogenic gene expression, and suggest a possible molecular mechanism linking NE differentiation and the increased metastatic potential of androgen-insensitive prostate cancers.

Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor.

Gastrin is a hormone produced by G-cells in the normal gastric antrum. However, colorectal carcinoma cells may aberrantly produce gastrin and exhibit increased expression of cholecystokinin B (CCK-B)/gastrin receptors. Gastrin is trophic for the normal gastric oxyntic mucosa and exerts a growth-promoting action on gastrointestinal malignancy. Thus, gastrin may act as an autocrine/paracrine or endocrine factor in the initiation and progression of colorectal carcinoma. The molecular mechanisms involved have not been elucidated. Hypergastrinemia induced by Helicobacter pylori infection is associated with increased cyclooxygenase-2 (COX-2) expression in gastric and colorectal tissues, suggesting the possibility that gastrin up-regulates COX-2 expression in these tissues; this has not been confirmed. We report here that gastrin significantly increases the expression of COX-2 mRNA and protein, the activity of the COX-2 promoter, and the release of prostaglandin E(2) from a rat intestinal epithelial cell line transfected with the CCK-B receptor. These actions were dependent upon the activation of multiple MAPK signal pathways, including ERK5 kinase; transactivation of the epidermal growth factor receptor; and the increased expression and activities of transcription factors ELK-1, activating transcription factor-2, c-Fos, c-Jun, activator protein-1, and myocyte enhancer factor-2. Thus, our findings identify the signaling pathways coupling the CCK-B receptor with up-regulation of COX-2 expression. This effect may contribute to this hormone-dependent gastrointestinal carcinogenesis, especially in the colon.

Bcl-2 overexpression increases survival in human retinal pigment epithelial cells exposed to H(2)O(2).

The integrity of the retinal pigment epithelium, especially that of the macula is essential for the preservation of vision into old age. The chronic exposure to sunlight and peroxidized lipids from phagocytized photoreceptor outer segments imposes a high level of oxidative stress on the retinal tissues, which increases with age as antioxidant protection declines and therefore could accelerate apoptosis. Bcl-2 known to facilitate mitochondrial DNA repair and cellular survival in other tissues was overexpressed in a single clone of human retinal pigment epithelium cells after stable transfection with humanbcl-2 in rhoSFV-neoexpression factor. Near confluent cells (2nd-4th generation permanently bcl-2 transfected) were protected from mitochondrial dysfunction after exposure to H(2)O(2) up to 150 microM. With 200 microM H(2)O(2), function in transfected cells declined by only 25% control activity as determined by MTT reduction assays, compared to wild type and vector only transfected cells expressing normal bcl-2 levels. Similarly the bcl-2 -transfected cells were more resistant to mitochondrial DNA damage after H(2)O(2) treatment than the other groups and suffered 50% less damage after exposure to 200 microM H(2)O(2), as assayed by quantitative polymerase chain reaction assays. These data suggest that bcl-2 overexpression protects human RPE cells from mitochondrial respiratory dysfuction, mitochondrial DNA damage and promotes cellular survival in response to oxidative stress induced by H(2)O(2).