Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis

Cell Death & Disease
Min Ji SeoKyeong Sook Choi

Abstract

Gambogic acid (GA), a xanthonoid extracted from the resin of the tree, Garcinia hanburyi, was recently shown to exert anticancer activity in multiple studies, but the underlying action mechanism remains unclear. Here, we show that GA induces cancer cell death accompanied by vacuolation in vitro and in vivo. This GA-induced vacuolation in various cancer cells was derived from dilation of the endoplasmic reticulum (ER) and mitochondria, and was blocked by cycloheximide. These findings suggest that GA kills cancer cells by inducing paraptosis, a vacuolization-associated cell death. We found that megamitochondria formation, which arose from the fusion of swollen mitochondria, preceded the fusion of ER-derived vacuoles. GA-induced proteasomal inhibition was found to contribute to the ER dilation and ER stress seen in treated cancer cells, and megamitochondria formation was followed by mitochondrial membrane depolarization. Interestingly, GA-induced paraptosis was effectively blocked by various thiol-containing antioxidants, and this effect was independent of ROS generation. We observed that GA can react with cysteinyl thiol to form Michael adducts, suggesting that the ability of GA to covalently modify the nucleophilic cysteinyl gro...Continue Reading

References

Apr 1, 1970·The Biochemical Journal·P J Anderson, R N Perham
Dec 20, 2000·Proceedings of the National Academy of Sciences of the United States of America·S SperandioD E Bredesen
Jan 16, 2004·Bioorganic & Medicinal Chemistry·Han-Zhong ZhangSui Xiong Cai
Apr 13, 2004·Oncogene·Judith Henry-MowattDominic James
Jun 15, 2004·Cell Death and Differentiation·S SperandioD E Bredesen
Aug 17, 2005·Proceedings of the National Academy of Sciences of the United States of America·Shailaja KasibhatlaBen Tseng
Dec 6, 2005·Biological & Pharmaceutical Bulletin·Quan-Bin HanHong-Xi Xu
Nov 15, 2006·Cancer Biology & Therapy·Ryungsa KimKazuaki Tanabe
Feb 22, 2012·Anti-cancer Agents in Medicinal Chemistry·Xu Wang, Wantao Chen
Oct 12, 2012·Annals of the New York Academy of Sciences·Dong Hoon SuhYong Sang Song
Jan 1, 2013·Acta Pharmacologica Sinica·Li-jing Yang, Yan Chen
Dec 18, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xianping ShiJinbao Liu
May 16, 2014·Cancer Cell·Hanna J ClarkeStefan J Marciniak
May 6, 2015·Seminars in Cancer Biology·Ramzi M MohammadAsfar S Azmi
Jun 3, 2015·World Journal of Gastroenterology : WJG·Guang-Ming HuangChun-Bo Li
Jul 6, 2015·Biochimica Et Biophysica Acta·Natalie Al-FuroukhThomas Braun
Aug 9, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Anne O Oyewole, Mark A Birch-Machin
Jan 24, 2016·Pharmacology & Therapeutics·Dongjoo LeeKyeong Sook Choi
Jul 29, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kendrick H YimLeonard Neckers
Aug 12, 2017·Experimental & Molecular Medicine·Dong Min LeeKyeong Sook Choi

❮ Previous
Next ❯

Citations

Dec 4, 2020·International Journal of Nanomedicine·Xiaowei WangRongguang Shao
Sep 28, 2020·Medicinal Research Reviews·Junmin ZhangJianguo Fang
Feb 8, 2021·Apoptosis : an International Journal on Programmed Cell Death·Xiaoli LiuLiang Zhang
Feb 16, 2021·Frontiers in Cell and Developmental Biology·Eunhee KimKyeong Sook Choi

❮ Previous
Next ❯

Methods Mentioned

BETA
xenograft
confocal
flow cytometry
fluorescence microscopy
protein folding
electron microscopy
Michael addition
fluorescence-activated cell sorting

Software Mentioned

GraphPad Prism
IncuCyte
IncuCyte ZOOM

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.