Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells.
The adverse side-effects associated with chemotherapy during cancer treatment have shifted considerable focus towards therapies that are targeted but devoid of toxic side-effects. In the present study, the antitumorigenic activity of thuja, the bioactive derivative of the medicinal plant Thuja occidentalis, was evaluated, and the molecular mechanisms underlying thuja-induced apoptosis of functional p53-expressing mammary epithelial carcinoma cells were elucidated. Our results showed that thuja successfully induced apoptosis in functional p53-expressing mammary epithelial carcinoma cells. Abrogation of intracellular reactive oxygen species (ROS), prevention of p53-activation, knockdown of p53 or inhibition of its functional activity significantly abridged ROS generation. Notably, under these conditions, thuja-induced breast cancer cell apoptosis was reduced, thereby validating the existence of an ROS-p53 feedback loop. Elucidating this feedback loop revealed bi-phasic ROS generation as a key mediator of thuja-induced apoptosis. the first phase of ROS was instrumental in ensuring activation of p53 via p38MAPK and its nuclear translocation for transactivation of Bax, which induced a second phase of mitochondrial ROS to construct the ROS-p53 feedback loop. Such molecular crosstalk induced mitochondrial changes i) to maintain and amplify the thuja signal in a positive self-regulatory feedback manner; and ii) to promote the mitochondrial death cascade through cytochrome c release and caspase-driven apoptosis. These results open the horizon for developing a targeted therapy by modulating the redox status of functional p53-expressing mammary epithelial carcinoma cells by thuja.
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, India.
Shilpi
S
Saha
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, India.
Pushpak
P
Bhattacharjee
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, India.
Shravanti
S
Mukherjee
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, India.
Minakshi
M
Mazumdar
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, India.
Samik
S
Chakraborty
Central Council for Research in Homeopathy, 61-65 Institutional Area, Janakpuri, New Delhi 110058, India.
Anil
A
Khurana
Central Council for Research in Homeopathy, 61-65 Institutional Area, Janakpuri, New Delhi 110058, India.
Debadatta
D
Nayak
Central Council for Research in Homeopathy, 61-65 Institutional Area, Janakpuri, New Delhi 110058, India.
Rajkumar
R
Manchanda
Bholanath Chakrabarty Trust, 5 Subol Koley Lane, Howrah 711101, India.
Rathin
R
Chakrabarty
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, India.
Tanya
T
Das
Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, India.
Gaurisankar
G
Sa
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008517:Phytotherapy / Q000379:methods; D010936:Plant Extracts / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D029783:Thuja; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53