Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells

  • Authors:
    • Shilpi Saha
    • Pushpak Bhattacharjee
    • Shravanti Mukherjee
    • Minakshi Mazumdar
    • Samik Chakraborty
    • Anil Khurana
    • Debadatta Nayak
    • Rajkumar Manchanda
    • Rathin Chakrabarty
    • Tanya Das
    • Gaurisankar Sa
  • View Affiliations

  • Published online on: January 24, 2014     https://doi.org/10.3892/or.2014.2993
  • Pages:1589-1598
0

Abstract

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.

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April 2014
Volume 31 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

2016 Impact Factor: 2.662
Ranked #31/217 Oncology
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APA
Saha, S., Bhattacharjee, P., Mukherjee, S., Mazumdar, M., Chakraborty, S., Khurana, A. ... Sa, G. (2014). Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells. Oncology Reports, 31, 1589-1598. https://doi.org/10.3892/or.2014.2993
MLA
Saha, S., Bhattacharjee, P., Mukherjee, S., Mazumdar, M., Chakraborty, S., Khurana, A., Nayak, D., Manchanda, R., Chakrabarty, R., Das, T., Sa, G."Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells". Oncology Reports 31.4 (2014): 1589-1598.
Chicago
Saha, S., Bhattacharjee, P., Mukherjee, S., Mazumdar, M., Chakraborty, S., Khurana, A., Nayak, D., Manchanda, R., Chakrabarty, R., Das, T., Sa, G."Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells". Oncology Reports 31, no. 4 (2014): 1589-1598. https://doi.org/10.3892/or.2014.2993