Caspase control: Protagonists of cancer cell apoptosis

Department of Molecular and Cellular Biochemistry and the Markey Cancer Center, University of Kentucky College of Medicine, Department of Urology, Lexington, KY 40536, USA.
Experimental oncology 10/2012; 34(3):165-75.
Source: PubMed

ABSTRACT Emergence of castration-resistant metastatic prostate cancer is due to activation of survival pathways, including apoptosis suppression and anoikis resistance, and increased neovascularization. Thus targeting of apoptotic players is of critical significance in prostate cancer therapy since loss of apoptosis and resistance to anoikis are critical in aberrant malignant growth, metastasis and conferring therapeutic failure. The majority of therapeutic agents act through intrinsic mitochondrial, extrinsic death receptor pathways or endoplasmic reticulum stress pathways to induce apoptosis. Current therapeutic strategies target restoring regulatory molecules that govern the pro-survival pathways such as PTEN which regulates AKT activity. Other strategies focus on reactivating the apoptotic pathways either by down-regulating anti-apoptotic players such as BCL-2 or by up-regulating pro-apoptotic protein families, most notably, the caspases. Caspases are a family of cystine proteases which serve critical roles in apoptotic and inflammatory signaling pathways. During tumorigenesis, significant loss or inactivation of lead members in the caspase family leads to impairing apoptosis induction, causing a dramatic imbalance in the growth dynamics, ultimately resulting in aberrant growth of human cancers. Recent exploitation of apoptosis pathways towards re-instating apoptosis induction via caspase re-activation has provided new molecular platforms for the development of therapeutic strategies effective against advanced prostate cancer as well as other solid tumors. This review will discuss the current cellular landscape featuring the caspase family in tumor cells and their activation via pharmacologic intervention towards optimized anti-cancer therapeutic modalities. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

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    • "Many chemical reagents, oxidative stress, alcohol , and other cellular stresses can trigger ER stress-induced apoptosis (Gorman et al. 2012). Caspases, which are closely associated with apoptosis, are aspartate-specific cysteine proteases regulated by the Bcl-2 family, calpain, and Ca 2? ions (Fiandalo and Kyprianou 2012; Smith and Schnellmann 2012). The intraluminal ER chaperone BiP is a member of the heat shock protein family and is a potent regulator of the ER stress mediators ATF6, PERK, and IRE1. "
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    • "Mutations, deletions or silencing of PTEN cause increases in the PI3K signal, which in turn stimulate downstream Akt signaling leading to promotion of growth factorindependent growth and increased cell invasion and metastasis (Hafsi et al. 2012). Activated Akt is a well-established survival factor, exerting anti-apoptotic activity by preventing the release of cytochrome C from mitochondria and inactivating Forkhead transcription factors (FKHR), which are known to induce the expression of genes that are critical for apoptosis (Fukunaga and Shioda 2009; Fiandalo and Kyprianou 2012). We have recent evidence to indicate that the down-regulation of Hsp27 (HSPB1) in MCF-7 human breast cancer cells induces upregulation of PTEN and reduces p-Akt levels (Cayado- Gutiérrez et al. 2012). "
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