A combined approach against tumorigenesis using glucose deprivation and mitochondrial complex 1 inhibition by rotenone.
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.
Biochemistry and Environmental Toxicology, , Laboratory # 103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Nupur Rani
NR
Agarwal
Biochemistry and Environmental Toxicology, , Laboratory # 103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Nancy
N
Maurya
Biochemistry and Environmental Toxicology, , Laboratory # 103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Jogendra Singh
JS
Pawar
Biochemistry and Environmental Toxicology, , Laboratory # 103, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Ilora
I
Ghosh
D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016922:Cellular Senescence / Q000187:drug effects; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005947:Glucose / Q000008:administration & dosage / Q000172:deficiency*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D017382:Reactive Oxygen Species; D012402:Rotenone; D053148:Caspase 3; D020169:Caspases; D042967:Electron Transport Complex I; D005947:Glucose
HeLa cell line; apoptosis; hyaluronan; oxidative stress; rotenone; senescence