oligomycins and Colorectal-Neoplasms

Forkhead box class O6 (FOXO6) is an important member of FOXO family, which has been demonstrated to be implicated in tumor development. However, the role of FOXO6 in colorectal cancer (CRC) is still unclear. The study aimed to investigate the potential roles of FOXO6 in the development of CRC. Our results showed that FOXO6 was overexpressed in CRC tissues and cell lines. FOXO6 knockdown inhibited cell proliferation, as well as repressed the migration and invasion of CRC cells. Additionally, we found that FOXO6 knockdown altered cellular metabolism by inhibiting glycolysis and promoting mitochondrial respiration. Furthermore, FOXO6 knockdown inhibited the activation of PI3K/Akt/mTOR pathway in CRC cells. The results herein indicated that FOXO6 knockdown inhibited cell proliferation, migration, invasion, and glycolysis in CRC cells. PI3K/Akt/mTOR pathway was involved in the effects of FOXO6 on CRC cells. These findings suggested that FOXO6 might be a potential target for the CRC therapy.

Topics: Caco-2 Cells; Cell Movement; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Glucose; Glycolysis; HCT116 Cells; HT29 Cells; Humans; Neoplasm Invasiveness; Oligomycins; Oxidative Phosphorylation; Oxygen Consumption; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; Signal Transduction; TOR Serine-Threonine Kinases

Frequently present in pancreatic, colorectal and non-small cell lung carcinomas, oncogenic mutant K-Ras must be localised to the plasma membrane (PM) to be functional. Inhibitors of K-Ras PM localisation are therefore putative cancer chemotherapeutics. By screening a microbial extract library in a high content cell-based assay we detected the rare oligomycin class of Streptomyces polyketides as inhibitors of K-Ras PM localisation. Cultivation and fractionation of three unique oligomycin producing Streptomyces strains yielded oligomycins A-E (1-5) and 21-hydroxy-oligomycin A (6), together with the new 21-hydroxy-oligomycin C (7) and 40-hydroxy-oligomycin B (8). Structures for 1-8 were assigned by detailed spectroscopic analysis. Cancer cell viability screening confirmed 1-8 were cytotoxic to human colorectal carcinoma cells (IC50 > 3 μM), and were inhibitors of the ABC transporter efflux pump P-glycoprotein (P-gp), with 5 being comparable in potency to the positive control verapamil. Significantly, oligomycins 1-8 proved to be exceptionally potent inhibitors of K-Ras PM localisation (Emax 0.67-0.75 with an IC50 ~ 1.5-14 nM).

Topics: Animals; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Dogs; Dose-Response Relationship, Drug; Humans; Madin Darby Canine Kidney Cells; Oligomycins; Protein Transport; ras Proteins; Structure-Activity Relationship