Background: Ethanol-induced neuronal apoptosis causes brain shrinkage and cognitive defects. Results: Exposure to ethanol (0.5% v/v for 72 h) in SH-SY5Y cells induced expression of miR-497 and miR-302b and downregulated expression of BCL2 and/or cyclin D2. Conclusion: Ethanol-induced neuronal apoptosis follows both the mitochondria-mediated and non-mitochondria-mediated pathways. Significance: Our study shows that miRNAs are involved in regulation of ethanol neurotoxicity.

Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.

Estrogen receptors (ERs) including ERα and ERβ are known to regulate multiple biological responses in various cell-types. The expression of ERβ is lost in various cancers. ERβ-agonists were shown to modulate inflammation, cancer cell proliferation and differentiation. Here, we investigated the cancer chemopreventive properties of Erb-041, an ERβ agonist employing a model of UVB-induced photocarcinogenesis in SKH-1 mice. Erb-041 significantly reduced UVB-induced carcinogenesis. Tumor numbers and volume were reduced by 60% and 84%, respectively in Erb-041-treated group as compared to UVB (alone) control. This inhibition in tumorigenesis was accompanied by the decrease in PCNA, cyclin D1, VEGF and CD31; and increase in apoptosis. The lost ERβ expression in SCCs was significantly recovered by Erb-041 treatment. Additionally, the UVB-induced inflammatory responses were remarkably reduced. Myeloperoxidase activity; levels of cytokines IL1β, IL6 and IL10; and expression of p-ERK1/2, p-p38, p-IκB, iNOS, COX-2 and nuclear NFκBp65 were diminished. The number of tumor-associated inflammatory cells (GR-1+/CD11b+ and F4/80+) was also decreased. Tumors excised from Erb-041-treated animal were less invasive and showed reduced epithelial-mesenchymal transition (EMT). The enhanced expression of E-cadherin with the concomitantly reduced expression of N-Cadherin, Snail, Slug and Twist characterized these lesions. WNT/β-catenin signaling pathway, which underlies pathogenesis of skin cancer was found to be down-regulated by Erb-041 treatment. Similar but not identical changes in proliferation and EMT regulatory proteins were noticed following treatment of tumor cells with a WNT-signaling inhibitor XAV939. Our results show that Erb-041 is a potent skin cancer chemopreventive agent which acts by dampening WNT/β-catenin signaling pathway.

Most non-small cell lung cancers (NSCLCs) contain non-targetable mutations, including KRAS, TP53 or STK11/LKB1 alterations. By coupling ex vivo drug sensitivity profiling with in vivo drug response studies, we aimed to identify drug vulnerabilities for these NSCLC subtypes. Primary adenosquamous carcinoma (ASC) or adenocarcinoma (AC) cultures were established from Kras G12D ;Lkb1 fl/fl (KL) tumors or AC cultures from Kras G12D ;p53 fl/fl (KP) tumors. While p53 null cells readily propagated as conventional cultures, Lkb1 null cells required conditional reprograming for establishment. Drug response profiling revealed short-term response to MEK inhibition, yet, long-term clonogenic assays demonstrated resistance, associated with sustained or adaptive activation of receptor tyrosine kinases (RTKs): activation of ERBBs in KL cultures, or FGFR in AC cultures. Furthermore, pan-ERBB inhibition reduced the clonogenicity of KL cultures, which was exacerbated by combinatorial MEK inhibition, while combinatorial MEK and FGFR inhibition suppressed clonogenicity of AC cultures. Importantly, in vivo studies confirmed KL-selective sensitivity to pan-ERBB inhibition, which correlated with high ERBB ligand expression and activation of ERBB receptors, implying that ERBB network activity may serve as a predictive biomarker of drug response. Interestingly, in human NSCLCs, phosphorylation of EGFR or ERBB3 was frequently detected in ASCs and squamous cell carcinomas. We conclude that analysis of in situ ERBB signaling networks in conjunction with ex vivo drug response profiling and biochemical dissection of adaptive RTK activities may serve as valid diagnostic approach to identify tumors sensitive to ERBB network inhibition.