Ginger extract activates caspase independent paraptosis in cancer cells via ER stress, mitochondrial dysfunction, AIF translocation and DNA damage

Abstract

The rhizome of ginger (Zingiber officinale) a common culinary agent is also known for its medicinal activity. We have earlier reported that pure 6-shogaol, an important component of ginger induces paraptosis in triple negative breast cancer (MDA-MB-231) and non small cell lung (A549) cancer cells. However, the chemopreventive potential of the whole ginger extract in food remains to be elucidated. Here, we demonstrate for the first time that ginger extract (GE) triggers similar anticancer activity/paraptosis against the same cell lines but through different molecular mechanisms. Q-TOF LC-MS analysis of the extract showed the presence of several other metabolites along with 6-shogaol and 6-gingerol. GE induces cytoplasmic vacuolation through ER stress and dilation of the ER. Drastic decrease in the mitochondrial membrane potential and ATP production along with the excess generation of ROS contributed to mitochondrial dysfunction. Consequently, GE caused the translocation of apoptosis inducing factor to the nucleus leading to the fragmentation of DNA. Taken together, these show a novel mechanism for ginger extract induced cancer cell death that can be of potential interest for cancer preventive strategies.

Acknowledgments

We are thankful to Dr. Nanjan Pandurangan for his help during ginger extract preparation; Dr. Walter Schrenk for several UHPLC and Mass Spectrometric analysis of the ginger extracts at the Amrita Agilent Analytical Research Center at Amrita Vishwa Vidyapeetham. We are also grateful to Dr. Raja Biswas, Center for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham for his advice and help.

Author contributions

NM and DN participated in research design; DN, AB: conducted experiments and assays; VV: imaging of immunofluorescence samples; MV, SSN: performed mass spectrometric analysis of the extract; DN, NM: writing of the manuscript; NM, DN, AB, SSN and BGN: editing of the manuscript.

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

The data generated and analyzed during the current study is available from the corresponding author on reasonable request.

Additional information

Funding

DN is thankful to Indian Council of Medical Research, India for her JRF/SRF fellowship (20097) and AB is thankful to University Grants Commission, India for her JRF/SRF fellowship [F.2/2012(SA-I)]. NM is thankful to Department of Science and Technology, India for support through research grant (DST: SB/FT/LS-144/2012).