akt-i-1-2-compound and Glioblastoma

Oct4 protein encoded by POU5F1 plays a pivotal role in maintaining the self‑renewal of pluripotent stem cells; however, its presence in cancer cells remains controversial. In the present study, we provided evidence that the transcripts of authentic OCT4 gene (OCT4A) and its multiple pseudogenes were detected in a variety of cancer cell lines. A few major bands were also detected by western blotting using an anti‑Oct4A monoclonal antibody. Moreover, an anti‑Oct4‑pT235 antibody was used to identify a band in the majority of the tested cancer cell lines that coincided with one of the anti‑Oct4A bands which was decreasable by a specific shRNA. The Oct4‑pT235 signals were also detected in human glioblastoma and liver cancer specimens by immunofluorescence microscopy and immunohistochemistry. U87 glioblastoma cells were cultured in a neural stem cell medium to induce the formation of neurospheres rich in stem‑like cancer cells. The levels of Oct4‑pT235 in the sphere cells were markedly increased compared to their monolayer parental cells, a result that was accompanied by upregulation of the PI3K‑Akt pathway. Akti‑1/2, a specific inhibitor of Akt, effectively reduced the level of Oct4‑pT235 and attenuated the proliferation of U87 sphere cells. ITE, an agonist of the aryl hydrocarbon receptor, also significantly attenuated the Akt‑mediated phosphorylation of Oct4 in glioblastoma and liver cancer cells, and reduced their tumorigenic potential in a xenograft tumor model. Taken together, we concluded that the Akt‑mediated phosphorylation of Oct4A or its homolog protein was associated with the proliferation of stem‑like cancer cells that may serve as a novel biomarker and drug target for certain types of cancer.

Topics: Animals; Benzylamines; Brain Neoplasms; Carcinoma, Hepatocellular; Cell Division; Cell Line, Tumor; Cell Nucleus; Culture Media; Glioblastoma; Heterografts; Humans; Indoles; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Proteins; Neoplastic Stem Cells; Octamer Transcription Factor-3; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Quinoxalines; Receptors, Aryl Hydrocarbon; RNA Interference; RNA, Small Interfering; Signal Transduction; Spheroids, Cellular; Thiazoles

Glioblastoma (GBM) is the most frequent and lethal brain cancer. The lack of early detection methods, the presence of rapidly growing tumor cells, and the high levels of recurrence due to chemo- and radioresistance make this cancer an extremely difficult disease to treat. Emerging studies have focused on inhibiting AKT activation; here, we demonstrate that in primary GBM tumor samples, full-dose inhibition of AKT activity leads to differential responses among samples in the context of cell death and self-renewal, reinforcing the notion that GBM is a heterogeneous disease. In contrast, low-dose AKT inhibition when combined with fractionation of radiation doses leads to a significant apoptosis-mediated cell death of primary patient-derived GBM cells. Therefore, low-dose-targeted therapies might be better for radiosensitization of primary GBM cells and further allow for reducing the clinical toxicities often associated with targeting the AKT/PI3K/mTOR pathway. This work emphasizes the discrepancies between cell lines and primary tumors in drug testing, and indicates that there are salient differences between patients, highlighting the need for personalized medicine in treating high-grade glioma.

Topics: Adult; Aged; Apoptosis; Benzimidazoles; Brain Neoplasms; Cell Survival; Dose-Response Relationship, Drug; Female; Glioblastoma; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplastic Stem Cells; Precision Medicine; Proto-Oncogene Proteins c-akt; Quinoxalines; Radiation-Sensitizing Agents; Tumor Cells, Cultured