Caspase control: Protagonists of cancer cell apoptosis
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".
- SourceAvailable from: Kyung Mi Yang
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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. "
ABSTRACT: Small-sized particles are more suitable for targeted delivery and are therapeutically more effective than large-sized particles. In this study, we investigated the anticancer effects of ultrafine particles of Ulmus davidiana var. japonica (ufUJ) on human gastric cancer cell lines SNU-1, SNU-216, and SNU-484. ufUJ induced apoptosis by the proteolytic activation of caspase-9, caspase-6, and caspase-3 and cleavage of poly (ADP-ribose) polymerase. The expression levels of the endoplasmic reticulum stress-related protein BiP markedly increased after ufUJ treatment. BiP knockdown decreased ufUJ-induced cell death. ufUJ-induced apoptosis was inhibited by the caspase-3 inhibitor z-DEVD-fmk, caspase-6 inhibitor z-VEID-fmk, and caspase-9 inhibitor z-LEHD-fmk, and by siRNAs against caspases 3, 6, and 9. Gastric cancer cells did not show anchorage-independent growth in the presence of ufUJ. However, cells treated with caspase inhibitors showed an enhanced colony-forming ability. These findings may be helpful in the prevention of gastric cancer and in the development of functional foods.Archives of Pharmacal Research 01/2014; 37(6). DOI:10.1007/s12272-013-0312-2 · 1.75 Impact Factor
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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). "
ABSTRACT: In a recent study, we have shown that in mammary tumors from mice lacking the Cav-1 gene, there are alterations in specific heat shock proteins as well as in tumor development. With this in mind, we have now investigated other proteins in the same mammary mouse tumor model (Her-2/neu expressing mammary tumors from Cav-1 wild type and Cav-1 null mice), to further comprehend the complex tumor-stroma mechanisms involved in regulating stress responses during tumor development. In this tumor model the cancer cells always lacked of Cav-1, so the KO influenced the Cav-1 in the stroma. By immunohistochemistry, we have found a striking co-expression of β-catenin and Her-2/neu in the tumor cells. The absence of Cav-1 in the tumor stroma had no effect on expression or localization of β-catenin and Her-2/neu. Both proteins appeared co-localized at the cell surface during tumor development and progression. Since Her-2/neu activation induces MTA1, we next evaluated MTA1 in the mouse tumors. Although this protein was found in numerous nuclei, the absence of Cav-1 did not alter its expression level. In contrast, significantly more PTEN protein was noted in the tumors lacking Cav-1 in the stroma, with the protein localized mainly in the nuclei. P-Akt levels were relatively low in tumors from both Cav-1 WT and Cav-1 KO mice. There was also an increase in nuclear NHERF1 expression levels in the tumors arising from Cav-1 KO mice. The data obtained in the MMTV-neu model are consistent with a role for Cav-1 in adjacent breast cancer stromal cells in modulating the expression and localization of important proteins implicated in tumor cell behavior.Cell Stress and Chaperones 02/2013; 18(5). DOI:10.1007/s12192-013-0408-0 · 2.54 Impact Factor
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ABSTRACT: Inhibition of apoptosis leads to activation of cell survival factors (e.g., AKT) causes continuous cell proliferation in cancer. Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. A number of discoveries have clarified the molecular mechanism of apoptosis, thus clarifying the link between apoptosis and cell survival factors, which has a therapeutic outcome. Induction of apoptosis and inhibition of cell survival by anticancer agents has been shown to correlate with tumor response. Cellular damage induces growth arrest and tumor suppression by inducing apoptosis, necrosis and senescence; the mechanism of cell death depends on the magnitude of DNA damage following exposure to various anticancer agents. Apoptosis is mainly regulated by cell survival and proliferating signaling molecules. As a new therapeutic strategy, alternative types of cell death might be exploited to control and eradicate cancer cells. This review discusses the signaling of apoptosis and cell survival, as well as the potential contribution of marine bioactive compounds, suggesting that new therapeutic strategies might follow.International Journal of Molecular Sciences 02/2013; 14(2):2334-54. DOI:10.3390/ijms14022334 · 2.86 Impact Factor