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Expert Opin Drug Discov. 2009 Sep;4(9):907-21. doi: 10.1517/17460440903055032. Epub 2009 Jun 25.

Implications of endoplasmic reticulum stress, the unfolded protein response and apoptosis for molecular cancer therapy. Part II: targeting cell cycle events, caspases, NF-κB and the proteasome.

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1
Head, Molecular Oncology Research Programme, University of the Western Cape, Department of Medical BioSciences, Bellville, 7535, South Africa +27 21 959 2334 ; +27 959 1563 ; dhiss@uwc.ac.za.

Abstract

BACKGROUND:

Endoplasmic reticulum stress (ERS), the unfolded protein response (UPR) and apoptosis signal transduction pathways are fundamental to normal cellular homeostasis and survival, but are exploited by cancer cells to promote the cancer phenotype.

OBJECTIVE:

Collateral activation of ERS and UPR role players impact on cell growth, cell cycle arrest or apoptosis, genomic stability, tumour initiation and progression, tumour aggressiveness and drug resistance. An understanding of these processes affords promising prospects for specific cancer drug targeting of the ERS, UPR and apoptotic pathways.

METHOD:

This review (Part II of II) brings forward the latest developments relevant to the molecular connections among cell cycle regulators, caspases, NF-κB, and the proteasome with ERS and UPR signalling cascades, their functions in apoptosis induction, apoptosis resistance and oncogenesis, and how these relationships can be exploited for targeted cancer therapy.

CONCLUSION:

Overall, ERS, the UPR and apoptosis signalling cascades (the molecular therapeutic targets) and the development of drugs that attack these targets signify a success story in cancer drug discovery, but a more reductionist approach is necessary to determine the precise molecular switches that turn on antiapoptotic and pro-apoptotic programmes.

PMID:
23480539
DOI:
10.1517/17460440903055032
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