STIL Endows Oncogenic and Stem-Like Attributes to Colorectal Cancer Plausibly by Shh and Wnt Signaling.

The discovery of a potent gene regulating tumorigenesis and drug resistance is of high clinical importance. STIL is an oncogene; however, its molecular associations and role in colorectal oncogenesis are unknown. In this study, we have explored the role of STIL gene in tumorigenesis and studied its molecular targets in colorectal cancer (CRC). STIL silencing reduced proliferation and tumor growth in CRC. Further, STIL was found to regulate stemness markers CD133 and CD44 and drug resistant markers thymidylate synthase, ABCB1, and ABCG2 both in in-vitro and in-vivo CRC models. In addition, high expression of STIL mRNA was found to be associated with reduced disease-free survival in CRC cases. Interestingly, we observed that STIL-mediated regulation of stemness and drug resistant genes is not exclusively governed by Sonic hedgehog (Shh) signaling. Remarkably, we found STIL regulate ß-catenin levels through p-AKT, independent of Shh pathway. This partially answers Shh independent regulatory mechanism of cancer stem cell (CSC) markers by STIL. Our study suggests an instrumental role of STIL in molecular manifestation of CRC and progression.

Gallic acid attenuates cadmium mediated cardiac hypertrophic remodelling through upregulation of Nrf2 and PECAM-1signalling in rats.

Gallic acid (GA) is an abundant natural polyphenolic compound found in vegetable and fruits that reduces the cardiac disease risk factor. This study aims to evaluate GA's role on cadmium (Cd) induced cardiac remodelling in experimental rats. Male Wistar rats were exposed to Cd (15 ppm) in drinking water and administered with GA orally (15 mg/kg/d) for 60 days. The results showed that GA regulated the lipid profile and reduced the LDL to 57 % compared with Cd treated rats. GA inhibited cardiac marker enzymes activity of CK-NAC (to 72.7 %) and CK-MB (to 100.3 %). Moreover, GA attenuated lipid peroxidation and enhanced the cardiac glutathione S transferase (GST) activity (89.2 %), glutathione peroxidase (GPx) (87 %), superoxide dismutase (SOD) (88.4 %) and catalase (CAT) activity (86.5 %). Histopathological examination showed that GA impaired the ventricular hypertrophy and fibrotic proliferation induced by Cd in rats. The combination of GA + Cd, decreased the gene expression of ANP (1-fold), BNP (0.5-fold) and ß- MHC (0.9-fold). Furthermore, GA significantly reduced the expression of profibrotic (TGF-ß) and proinflammatory (MCP-1) gene in Cd intoxicated rats. GA upregulated the expression of Nrf2 (2-fold), HO-1 (3-fold), and PECAM-1 (0.6-fold), which augments the detoxifying enzyme activity and cellular immunity in Cd intoxicated rats. The increased protein expression of Nrf2, PECAM-1 and decreased AKT-1 levels confirmed the mechanical action of GA during the hypertrophic condition. Thus, our results suggest that GA could act as a potential therapeutic agent regulating Nrf2 and PECAM-1 signalling pathways, thereby ameliorating Cd-induced pathological cardiac remodelling.

Altered molecular pathways decides the treatment outcome of Hsp90 inhibitors against breast cancer cells.

The altered molecular pathways in response to chemotherapeutic interventions impose limitations on breast cancer treatments. Therefore, understanding the outcome of these alternative pathways may help in improving the chemotherapy. In this study, using hormone responsive and hormone independent breast cancer cells, MCF-7 and MDAMB-231 respectively, we studied some of the molecular pathways that contribute to cancer progression. Since the cancer chaperone, Hsp90 inhibitors have entered the clinical trials, we used Hsp90 inhibitor, 17AAG to examine the outcome of altered molecular pathways. The observed differential sensitivity in MCF7 and MDAMB-231 cells to 17AAG treatment is then attributed to both tumor microenvironment mediated by hypoxia and acquired alterations in the endogenous stem cell pool. Interestingly, tumor cells are able to retain epithelial characteristics in addition to gaining mesenchymal characteristics in response to 17AAG treatment. We observed MCF-7 cells exhibiting induced cellular differentiation, whereas MDAMB-231 cells exhibiting reduced cellular differentiation in response to 17AAG treatment. These changes are subsequently found to be the sporadic outcome of altered epigenetic landscape. The mice tumor xenograft studies have revealed that decreased metastatic potential of MCF-7 and increased metastatic potential with altered homing properties of MDAMB-231 are the outcome of altered molecular pathways. Our findings expose the interference of altered molecular pathways influencing the therapeutic outcome.

FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis.

Forkhead box transcription factor, FOXM1 is implicated in several cellular processes such as proliferation, cell cycle progression, cell differentiation, DNA damage repair, tissue homeostasis, angiogenesis, apoptosis, and redox signaling. In addition to being a boon for the normal functioning of a cell, FOXM1 turns out to be a bane by manifesting in several disease scenarios including cancer. It has been given an oncogenic status based on several evidences indicating its role in tumor development and progression. FOXM1 is highly expressed in several cancers and has also been implicated in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in angiogenesis, invasion, migration, self- renewal and drug resistance. In this review, we attempt to understand various mechanisms underlying FOXM1 gene and protein regulation in cancer including the different signaling pathways, post-transcriptional and post-translational modifications. Identifying crucial molecules associated with these processes can aid in the development of potential pharmacological approaches to curb FOXM1 mediated tumorigenesis.

Thiostrepton degrades mutant p53 by eliciting an autophagic response in SW480 cells.

Mutations in p53 gene are one of the hallmarks of tumor development. Specific targeting of mutant p53 protein has a promising role in cancer therapeutics. Our preliminary observation showed destabilization of mutant p53 protein in SW480, MiaPaCa and MDAMB231 cell lines upon thiostrepton treatment. In order to elucidate the mechanism of thiostrepton triggered mutant p53 degradation, we explored the impact of proteasome inhibition on activation of autophagy. Combined treatment of thiostrepton and cycloheximide/chloroquine prevented the degradation of mutant p53 protein, reinforcing autophagy as the means of mutant p53 destabilization. Our initial studies suggested that mutant p53 degradation post THSP treatment was carried out by BAG3 mediated autophagy, based on the evidence of BAG1 to BAG3 switching. Subsequent interactome analysis performed post thiostrepton treatment revealed an association of p53 with autophagosome complex associated proteins such as BAG3, p62 and HSC70. Reaccumulation of p53 was seen in BAG3 silenced cells treated with thiostrepton, thereby confirming the role of BAG3 in destabilization of this molecule. Further, localization of p53 into the lysosome upon THSP treatment substantiated our findings that mutant p53 was degraded by an autopahgic process.