Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells

Abstract

AKT serves as an epigenetic modulator that links epigenetic regulation to cell survival and proliferation while the epigenetic mediator OCT4 critically controls stem cell pluripotency and self-renewal. Emerging evidence indicated their complicated interplays in cancer cells and cancer stem cells (CSCs), and inhibiting either one may activate the other. Thus, in this study, we propose a strategy to targeting both factors simultaneously. Firstly, a combination of an OCT4-specific shRNA and the specific AKT inhibitor Akti-1/2 potently suppressed the propagation of human embryonal carcinoma cells, adherent cancer cells and stem-like cancer cells, establishing the proof-of-concept that dual inhibiting OCT4 and AKT can effectively target various cancer cells. Next, we combined Akti-1/2 with metformin, a widely-prescribed drug for treating type 2 diabetes, which was reported to down-regulate OCT4 expression. The metformin + Akti-1/2 combo significantly altered multiple signaling and epigenetic pathways, induced growth arrest and cell death of adherent and stem-like glioblastoma U87 cells, and attenuated their tumorigenicity in vivo. Taken together, we demonstrate here that simultaneously targeting an epigenetic mediator and an epigenetic modulator, by dual inhibiting OCT4 and AKT, can have significantly improved efficacies over single treatment in suppressing the propagation of CSCs as well as the entire bulk of differentiated cancer cells.

Endogenous authentic OCT4A proteins directly regulate FOS/AP-1 transcription in somatic cancer cells

“…We then examined OCT4A protein in the above cells by regular western blotting (WB) analysis using a rabbit monoclonal antibody presumed to be OCT4A-specific (CST 2890). Similar to previous results from our own group 25 , 28 , 29 and other groups 30 – 32 , we detected two major bands with apparent molecular size of 50 kDa (blue arrow, Fig. 2a ) and 43 kDa (black arrow, Fig.…”

“…We then asked if OCT4A plays a definitive role in anticancer drug resistance, as multiple studies have indicated its involvement in promoting cellular resistance to chemotherapy based on RNAi strategies that were not specifically targeting OCT4A 25 , 29 , 43 , 44 . We treated the WT and OCT4A-KO cells with Cisplatin, a first-line anticancer drug for cervical carcinoma, or Akti-1/2, a potent anticancer agent in clinical trial.…”

Correlation of Cancer Stem-Cell Markers OCT4, SOX2, and NANOG with Clinicopathological Features and Prognosis in Operative Patients with Rectal Cancer

“… 22 23 24 25 Secondly, OCT4 expression regulates multiple signalling pathways, including p38 mitogen-activated protein kinase (MAPK)/caspase-3, Wnt/β-catenin, AKT, and Janus Kinase (JAK)/signal transducer and activator of transcription (STAT)3 signal pathways, thereby resulting in the promotion of tumorigenesis and malignant transformation, and increase of recurrences. 26 27 28 29 …”

Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth

“…Considering the many functions of mTOR, such as sensing metabolic changes, these results and studies implicate HSF1 in many functions of cancer cell biology and a significant interplay between PI3K/AKT signaling, mTOR signaling, and HSF1 activity. Other studies have shown that targeting OCT4 [ 40 ], p70S6K [ 41 ], MAP kinase components [ 42 , 43 ], IGF-1R [ 44 ], and HER2 [ 45 ] may also be co-targets of PI3K/AKT that show efficacy. Our results indicate another molecular in HSF1 that could also be a potential co-target with PI3K/AKT.…”