Cycloheximide promotes paraptosis induced by inhibition of cyclophilins in glioblastoma multiforme

Cell Death & Disease
Lin WangRichard J Bram

Abstract

Cancer is the second leading cause of death worldwide. Current treatment strategies based on multi-agent chemotherapy and/or radiation regimens have improved overall survival in some cases. However, resistance to apoptosis often develops in cancer cells, and its occurrence is thought to contribute to treatment failure. Non-apoptotic cell death mechanisms have become of great interest, therefore, in hopes that they would bypass tumor cell resistance. Glioblastoma multiforme (GBM), a grade IV astrocytic tumor is the most frequent brain tumor in adults, and has a high rate of mortality. We report that NIM811, a small molecule cyclophilin-binding inhibitor, induces catastrophic vacuolization and cell death in GBM cells. These unique features are distinct from many known cell death pathways, and are associated with an incompletely defined cell death mechanism known as paraptosis. We found that NIM811-induced paraptosis is due to unresolved ER stress. The abnormal upregulation of protein translation was responsible for the build-up of misfolded or unfolded proteins in ER, whereas pro-survival autophagy and UPR signals were shutdown during prolonged treatment with NIM811. Although cycloheximide has been claimed to suppress paraptosis,...Continue Reading

References

Sep 17, 1987·Nature·K LangG Fischer
Nov 30, 1993·Annals of the New York Academy of Sciences·G WiederrechtN Sigal
Jan 13, 1995·The Journal of Biological Chemistry·C J SabersR T Abraham
Jun 5, 1998·The Journal of Biological Chemistry·F PoulinN Sonenberg
Dec 20, 2000·Proceedings of the National Academy of Sciences of the United States of America·S SperandioD E Bredesen
Jul 11, 2001·Genes & Development·C U Hellen, P Sarnow
Jun 20, 2003·Apoptosis : an International Journal on Programmed Cell Death·T M CasertaT L Brown
Feb 12, 2005·World Journal of Surgery·Qizhi YaoChangyi Chen
Jul 2, 2005·Molecular Cell·Koichi WatashiKunitada Shimotohno
Jan 13, 2006·Nature Chemical Biology·Alexei DegterevJunying Yuan
Sep 23, 2006·Physiology·Xuemin Wang, Christopher G Proud
Jun 15, 2007·Nature Reviews. Molecular Cell Biology·David Ron, Peter Walter
Feb 26, 2008·Proceedings of the National Academy of Sciences of the United States of America·In Hye LeeToren Finkel
Dec 10, 2009·PLoS Genetics·Jae Won ChoiRichard J Bram
Jul 20, 2010·Journal of Experimental & Clinical Cancer Research : CR·Jinhwa Lee, Sung Soo Kim
Jul 5, 2013·Proceedings of the National Academy of Sciences of the United States of America·Egor SvidritskiyAndrei A Korostelev
Jul 11, 2013·PloS One·Chuanjiang HuangPengfei Ge
Jan 1, 2014·Wiley Interdisciplinary Reviews. RNA·Botao Liu, Shu-Bing Qian
Jul 22, 2014·The Journal of Law, Medicine & Ethics : a Journal of the American Society of Law, Medicine & Ethics·Susan V EllorNicholas G Avgeropoulos
Jan 24, 2016·Pharmacology & Therapeutics·Dongjoo LeeKyeong Sook Choi

❮ Previous
Next ❯

Citations

Feb 21, 2019·FEMS Yeast Research·A Ya ValiakhmetovA O Shepelyakovskaya
Aug 1, 2019·Expert Opinion on Biological Therapy·Lin WangJoseph C Wu
Dec 24, 2019·Expert Opinion on Investigational Drugs·Daren R UreRobert T Foster
Mar 1, 2020·Photochemistry and Photobiology·David Kessel
Nov 17, 2017·Photochemistry and Photobiology·David Kessel, Nancy L Oleinick
Oct 14, 2018·Biomolecules·Stefano Stifani
Mar 30, 2019·Photochemistry and Photobiology·David Kessel
Feb 6, 2019·Biomolecules·Nadia R ZgajnarMario D Galigniana
Feb 8, 2021·Apoptosis : an International Journal on Programmed Cell Death·Xiaoli LiuLiang Zhang

❮ Previous
Next ❯

Methods Mentioned

BETA
xenograft
RNA-seq
FACS
transfection
flow cytometry

Related Concepts

Related Feeds

Autophagy & Metabolism

Autophagy preserves the health of cells and tissues by replacing outdated and damaged cellular components with fresh ones. In starvation, it provides an internal source of nutrients for energy generation and, thus, survival. A powerful promoter of metabolic homeostasis at both the cellular and whole-animal level, autophagy prevents degenerative diseases. It does have a downside, however--cancer cells exploit it to survive in nutrient-poor tumors.

Astrocytes

Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Autophagy & Disease

Autophagy is an important cellular process for normal physiology and both elevated and decreased levels of autophagy are associated with disease. Here is the latest research.

Parkinson's Disease & Autophagy (MDS)

Autophagy leads to degradation of damaged proteins and organelles by the lysosome. Impaired autophagy has been implicated in several diseases. Here is the role of autophagy in Parkinson’s disease.