A combined approach against tumorigenesis using glucose deprivation and mitochondrial complex 1 inhibition by rotenone

• Published in: Cell biology international Vol. 40; no. 7; pp. 821 - 831
• Main Authors: Agarwal, Nupur Rani, Maurya, Nancy, Pawar, Jogendra Singh, Ghosh, Ilora
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2016; Wiley Subscription Services, Inc
• Subjects: apoptosis; Apoptosis - drug effects; Cancer; Cancer therapies; Carcinogenesis - drug effects; Carcinogenesis - metabolism; Caspase 3 - metabolism; Caspases - metabolism; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Survival - drug effects; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellular Senescence - drug effects; Electron Transport Complex I - antagonists & inhibitors; Electron Transport Complex I - metabolism; Glucose; Glucose - administration & dosage; Glucose - deficiency; HeLa cell line; HeLa Cells; Humans; hyaluronan; Mitochondria - drug effects; Mitochondria - metabolism; oxidative stress; Oxidative Stress - drug effects; Physiology; Reactive Oxygen Species - metabolism; rotenone; Rotenone - pharmacology; senescence; Signal Transduction - drug effects; HeLa cell line; senescence; rotenone; apoptosis; hyaluronan; oxidative stress
• ISSN: 1065-6995; 1095-8355
• DOI: 10.1002/cbin.10619

Cancer cells exhibit various degrees of mitochondrial metabolic alterations. Owing to their multiple roles, mitochondria are attractive target for cancer therapy. Cancerous cells have high glucose (HG) requirements for their growth. Depriving them of glucose has been an approach used in many studies to restrict their perpetuation. However, such deprivation can negatively affect the surrounding normal cells in vivo. Keeping this in view, we treated HeLa cells with only physiological glucose (PG, 5.5 mM) and a combination of physiological glucose with a very low dose (1 nM) of rotenone (PGT), taking high glucose (HG, 25 mM)‐treated HeLa cells as normal. We demonstrated that HeLa cells under PG condition mainly exhibited growth arrest. The PGT combination induced apoptosis in HeLa cells by generation of ROS, decrease in ATP production even with around 1.89‐fold increase in glucose consumption, cell cycle arrest at S‐phase and substantial increase in sub‐diploid (Sub‐D) population. The oxidative stress generated in both PG and PGT conditions stabilised p53 by localising it in the nuclei of HeLa cells, which would have otherwise undergone HPV‐mediated inactivation. Pre‐mature senescence induced due to limited glucose availability was found to be regulated by nuclear translocated p53 which, in turn, induced p21, pAkt and pERK. The cyto‐toxic effect of rotenone on glucose deprived HeLa cells, synergistically activated NFκB, caspase‐3 and Bax along with reduced expression of hyaluronan, a ROS scavenging molecule on their cell surface. Thus, our finding might be a valuable approach to specifically target cancerous cells in a more physiologically feasible condition and can serve as a relevant biochemical basis to gain new insights into cancer therapy.