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Exp Cell Res. 2018 Mar 15;364(2):243-251. doi: 10.1016/j.yexcr.2018.02.018. Epub 2018 Feb 17.

6-Shogaol induces caspase-independent paraptosis in cancer cells via proteasomal inhibition.

Author information

1
School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India.
2
School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O., Kollam 690525, Kerala, India. Electronic address: nanditamishra@am.amrita.edu.

Abstract

An α, β-unsaturated carbonyl compound of ginger, 6-Shogaol (6S), induced extensive cytoplasmic vacuolation and cell death in breast cancer cell (MDA-MB-231) and non-small lung cancer (A549) cells. In the presence of autophagic inhibitors the cells continued to exhibit cytoplasmic vacuolation and cell death clearly distinguishing it from the classic autophagic process. 6S induced death did not exhibit the characteristic apoptotic features like caspase cleavage, phosphatidyl serine exposure and DNA fragmentation. The immunofluorescence with the Endoplasmic Reticulum (ER) resident protein, calreticulin indicated that the vacuoles were of ER origin, typical of paraptosis. This was supported by the increase in level of microtubule associated protein light chain 3B (LC3 I and LC3 II) and polyubiquitin binding protein, p62. The level of ER stress markers like polyubiquitinated proteins, Bip and CHOP also consistently increased. We have found that 6S inhibits the 26S proteasome. The proteasomal inhibitory activity was elucidated by a) molecular docking of 6S onto the active site of β5 subunit and b) reduced fluorescence by the fluorogenic substrate of the chymotrypsin-like subunit. In conclusion these studies demonstrate for the first time that proteasomal inhibition by 6S induces cell death via paraptosis. So 6-shogaol may act as a template for anti-cancer lead discovery against the apoptosis resistant cancer cells.

KEYWORDS:

6-Shogaol; ER stress; Paraptosis; Proteasome inhibition; α, β-unsaturated carbonyl compound

PMID:
29462602
DOI:
10.1016/j.yexcr.2018.02.018
[Indexed for MEDLINE]

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