Gallic acid is claimed to possess antioxidant, antiinflammatory and cytoprotective effects. Since pancreatic islets from Type 2 diabetic patients have functional defects, it was hypothesized that glucolipotoxicity might induce apoptosis in beta-cells and gallic acid could offer protection. To test this, RINm5F beta-cells were exposed to high glucose (25 microM) or palmitate (500 microM) or a combination of both for 24 h in the presence and absence of gallic acid. Cells subjected to glucolipotoxicity in the absence and presence of gallic acid were assessed for DNA damage by comet assay. Apoptosis was inferred by caspase-3 protein expression and caspase-3 activity and changes in Bcl-2 mRNA. RT-PCR was used to analyse PDX-1, insulin and UCP-2 mRNA expression in RINm5F beta-cells and insulin levels were quantified from the cell culture supernatant. NFkappaB signal was studied by EMSA, immunofluorescence and Western blot analysis. While RINm5F beta-cells subjected to glucolipotoxicity exhibited increased DNA damage, apoptotic markers and NFkappaB signals, all these apoptotic perturbations were resisted by gallic acid. Gallic acid dose-dependently increased insulin secretion in RINm5F beta-cells and upregulated mRNA of PDX-1 and insulin. It is suggested that the insulin-secretagogue and transcriptional regulatory action of gallic acid is a newly identified mechanism in our study.

This study indicates that curcumin has an inhibitory effect on SDF-1alpha-induced HREC migration. The plausible mechanism of action could be upstream blockage of Ca(2+) influx and the downstream reduction of PI3-K/AKT signals.

Breast cancer (BC) is the most common cause of cancer-related death in females in Saudi Arabia. BC in Saudi women tend to behave more aggressively than breast cancer in the West. Therefore, identification of new molecular targets and treatment strategies are highly warranted to improve patient outcome. FoxM1 has been shown to play a critical role in pathogenesis of various malignancies. In this study, we explored the prevalence and clinical implication of FoxM1 overexpression in Saudi breast cancer. FoxM1 protein overexpression was seen in 79% (770/975) of BC tissues and was associated with aggressive clinical parameters such as younger age (< 30 yrs) (p = 0.0172), high grade (p < 0.0001), mucinous histology (p < 0.0001) and triple negative phenotype (p < 0.0001). Overexpression of FoxM1 was significantly associated with activated AKT (p < 0.0001), Ki67 expression (p < 0.0001), VEGF (p < 0.0001), MMP-9 (p < 0.0001), XIAP (p < 0.0001) and Bcl-xL (p = 0.0300). Importantly, FoxM1 overexpression is found to be an independent prognostic marker in multivariate analysis in advanced stage (Stage III and IV) breast cancer (p = 0.0298). In vitro data using BC cell lines showed that down-regulation of FoxM1 using specific inhibitor, thiostrepton or siRNA inhibited cell migration, invasion and angiogenesis. In addition, treatment of BC cell lines with thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. In vivo, thiostrepton treatment regressed MDA-MB-231 cells generated xenografts via down-regulation of FoxM1 and its downstream targets. Our results suggest that FoxM1 may be a potential therapeutic target for the treatment of aggressive breast cancers.

Colorectal cancer is one of the leading causes of cancerrelated deaths worldwide. In Saudi Arabia, colorectal cancer is more aggressive and presents at younger age, warranting new treatment strategies. Role of TGFb/Smad4 signaling pathway in initiation and progression of colorectal cancer is well documented. This study examined the role of TGFb/Smad4 signaling pathway in a large cohort of Saudi patients with colorectal cancer, followed by in vitro analysis to dissect the dual role of TGFb on inducing epithelial-to-mesenchymal transition (EMT) and apoptosis. Our study demonstrated high frequency of Smad4 alterations with low expression of Smad4 protein identifying a subgroup of aggressive colorectal cancer to be an independent marker for poor prognosis. Functional studies using colorectal cancer cells show that TGFb induces Smad4-dependent EMT followed by apoptosis. Induction of mesenchymal transcriptional factors, Snail1 and Zeb1, was essential for TGFb-induced apoptosis. Our results indicate that KLF5 acts as an oncogene in colorectal cancer cells regardless of Smad4 expression and inhibition of KLF5 is requisite for TGFb-induced apoptosis. Furthermore, TGFb/Smad4 signal inhibits the transcription of KLF5 that in turn switches Sox4 from tumor promoter to suppressor. A high incidence of Smad4 alterations were found in the Saudi patients with colorectal cancer. Functional study results indicate that TGFb induces Smad4-dependent EMT followed by apoptosis in colorectal cancer cells.

Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) are two key components of PI3K/Akt/mTOR signaling pathway. Dysregulation of these pathways have been found in many cancers, including epithelial ovarian cancer (EOC), however, the role of mTOR has not been fully elucidated in Middle Eastern EOC. Therefore, we investigated the activation of mTOR complexes (mTORC1 and mTORC2) in a cohort of 156 EOC from Saudi Arabia by immunohistochemistry in a tissue microarray format. mTORC1 and mTORC2 were found to be activated in 55 of 146 (37.7%) and 63 of 140 (45%) of EOC samples, respectively. mTORC1 was significantly associated with mTORC2 (p < 0.0001) activation and both mTOR complexes were significantly associated with p-AKT (p = 0.0205 and 0.0298) and p-P70S6 (p < 0.0001 and 0.0035), respectively. Interestingly, mTOR activation incurred a poor progression-free survival (PFS) (p = 0.0188) in EOC. Next, the in vitro effect of inactivation of mTOR complexes was evaluated using a second-generation mTOR inhibitor, Torin2, on a panel of EOC cell lines. Torin2 treatment decreased cell viability and induced apoptosis in a dose-dependent manner via inactivation of mTORC1 and mTORC2 and their downstream targets in EOC cell lines. Furthermore, treatment of EOC cells with a subtoxic dose of Torin2 potentiated a cisplatin-induced apoptotic response in EOC cell lines. Finally, we studied the in vivo effect of a combination of Torin2 and cisplatin and found that this combination synergistically inhibited tumor growth in nude mice. These studies highlight the importance of targeting the mTOR survival pathway and suggest that cotreatment with cisplatin and Torin2 may be beneficial for the management of EOC.