Baculovirus p35 and Z-VAD-fmk inhibit thapsigargin-induced apoptosis of breast cancer cells

Qi, Xiao Mei; He, Hao; Zhong, Hongying; Distelhorst, Clark W.

doi:10.1038/sj.onc.1201290

Cited by 41 publications

(24 citation statements)

References 24 publications

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“…TG, on the other hand, depletes the calcium pool of the ER. Both pathways activate GRP78, a chaperone protein (Gomer et al, 1991;Li et al, 1993) and can be blocked by overexpression of Bcl2 (He et al, 1996;Qi et al, 1997;Liu et al, 1997). We show here that Etk is able to protect LNCaP cells from apoptosis induced by either agent.…”

Section: Discussionsupporting

confidence: 48%

“…TG inhibits an ATP-gated calcium pump controlling the in¯ux of calcium from the cytosol to the endoplasmic reticulum (ER), thereby depleting the calcium pool of the ER and activating the apoptosis pathway . This process is accompanied by an induction of GRP78 expression and caspase activation, and cells can be rescued by overexpression of Bcl2 (Qi et al, 1997;Liu et al, 1997). Thus, although PDT and TG take di erent routes to initiate the apoptotic process, there is a converging of pathways in the downstream events of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Etk/Bmx, a PH-domain containing tyrosine kinase, protects prostate cancer cells from apoptosis induced by photodynamic therapy or thapsigargin

Xue

Qiu

et al. 1999

Oncogene

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Prostate carcinoma (PCA) is the most frequently diagnosed malignancy in American men. PCA at advanced stages can both proliferate abnormally and resist apoptosis. Among the many known signal transduction pathways, phosphatidylinositide-3'OH kinase (PI3-kinase) has been shown to play an important role in cell survival and resistance to apoptosis. In this study, we investigate the involvement of Etk/Bmx, a newly discovered tyrosine kinase that is a substrate of PI3-kinase, in protection of prostate cancer cells from apoptosis. Parental LNCaP cells and two derivative cell lines, one overexpressing wild type Etk (Etkwt) and the other expressing a dominant negative Etk (EtkDN), were used to study the function of Etk. The cells were treated with photodynamic therapy (PDT), a newly approved cancer treatment which employs a photosensitizer and visible light to produce an oxidative stress in cells, often leading to apoptosis. Our results indicate that PDT induces apoptosis in LNCaP cells, as measured by DNA fragmentation and by cleavage of poly(ADP-ribose) polymerase (PARP), and moreover, the extent of apoptosis was much reduced in Etkwt cells as compared to LNCaP or EtkDN cells. Assay of overall cell viability con®rmed that Etkwt cells were considerably less sensitive to PDT than were the parental LNCaP or EtkDN cells. Similar results were found in response to thapsigargin (TG). A speci®c inhibitor of PI3-kinase, LY294002, abolished Etk activity and markedly increased TG-induced PARP cleavage. The results suggest that Etk/Bmx is an e cient e ector of PI3-kinase and that the newly described PI3-kinase/Etk pathway is involved in the protection of prostate carcinoma cells from apoptosis in response to PDT or TG.

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Section: Discussionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Etk/Bmx, a PH-domain containing tyrosine kinase, protects prostate cancer cells from apoptosis induced by photodynamic therapy or thapsigargin

Xue

Qiu

et al. 1999

Oncogene

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“…Although MCF-7 cells treated with ␤-Lap had similar calcium responses, as do TG-exposed cells, ␤-Lap-exposed cells (28,33,34,54), an ATP-independent protease is activated after exposure to ␤-Lap. Ca 2ϩ may regulate apoptosis by activating Ca 2ϩ -dependent protein kinases and/or phosphatases leading to alterations in gene transcription.…”

Section: Camentioning

confidence: 91%

Calcium Is a Key Signaling Molecule in β-Lapachone-mediated Cell Death

Tagliarino¹,

Pink²,

Dubyak

et al. 2001

Journal of Biological Chemistry

153

150

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␤-Lapachone (␤-Lap) triggers apoptosis in a number of human breast and prostate cancer cell lines through a unique apoptotic pathway that is dependent upon NQO1, a two-electron reductase. Downstream signaling pathway(s) that initiate apoptosis following treatment with ␤-Lap have not been elucidated. Since calpain activation was suspected in ␤-Lap-mediated apoptosis, we examined alterations in Ca 2؉ homeostasis using NQO1-expressing MCF-7 cells. ␤-Lap-exposed MCF-7 cells exhibited an early increase in intracellular cytosolic Ca 2؉, from endoplasmic reticulum Ca 2؉ stores, comparable to thapsigargin exposures. 1,2-Bis-(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid-acetoxymethyl ester, an intracellular Ca 2؉ chelator, blocked early increases in Ca 2؉ levels and inhibited ␤-Lap-mediated mitochondrial membrane depolarization, intracellular ATP depletion, specific and unique substrate proteolysis, and apoptosis. The extracellular Ca 2؉ chelator, EGTA, inhibited later apoptotic end points (observed >8 h, e.g. substrate proteolysis and DNA fragmentation), suggesting that later execution events were triggered by Ca 2؉ influxes from the extracellular milieu. Collectively, these data suggest a critical, but not sole, role for Ca 2؉ in the NQO1-dependent cell death pathway initiated by ␤-Lap. Use of ␤-Lap to trigger an apparently novel, calpain-like-mediated apoptotic cell death could be useful for breast and prostate cancer therapy. ␤-Lap1 is a naturally occurring compound present in the bark of the South American Lapacho tree. It has antitumor activity against a variety of human cancers, including colon, prostrate, promyelocytic leukemia, and breast (1-3). ␤-Lap was an effective agent (alone and in combination with taxol) against human ovarian and prostate xenografts in mice, with little host toxicity (4). We recently demonstrated that ␤-Lap kills human breast and prostate cancer cells by apoptosis, a cytotoxic response significantly enhanced by NAD(P)H:quinone oxidoreductase (NQO1, E.C. 1.6.99.2) enzymatic activity (5).2 ␤-Lap cytotoxicity was prevented by co-treatment with dicumarol (an NQO1 inhibitor) in NQO1-expressing breast and prostate cancer cells (5).2 NQO1 is a cytosolic enzyme elevated in breast cancers (6) that catalyzes a two-electron reduction of quinones (e.g. ␤-Lap, menadione), utilizing either NADH or NADPH as electron donors. Reduction of ␤-Lap by NQO1 presumably leads to a futile cycling of the compound, wherein the quinone and hydroquinone form a redox cycle with a net concomitant loss of reduced NAD(P)H (5).Apoptosis is an evolutionarily conserved pathway of biochemical and molecular events that underlie cell death processes involving the stimulation of intracellular zymogens. The process is a genetically programmed form of cell death involved in development, normal turnover of cells, and in cytotoxic responses to cellular insults. Once apoptosis is initiated, biochemical and morphological changes occur in the cell. These changes include: DNA fragmentation, chromatin condensation, cytoplasmic membran...

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“…Because MCF-7 cells lack caspase-3, a cell-permeable tripeptide [Z-ValAla-Asp-fluoromethyl-ketone (Z-VAD-fmk)] that broadly inhibits multiple caspases was used to assess apoptosis (34). MCF-7 cells were seeded at 200,000 per well in a six-well plate.…”

Section: Methodsmentioning

confidence: 99%

Identification of Cyclin D1– and Estrogen-Regulated Genes Contributing to Breast Carcinogenesis and Progression

et al. 2006

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Tumors can become lethal when they progress from preinvasive lesions to invasive carcinomas. Here, we identify candidate tumor progression genes using gene array analysis of preinvasive and invasive tumors from mice, which were then evaluated in human cancers. Immediate early response protein IEX-1, small stress protein 1 (HSPB8), and tumor necrosis factorassociated factor-interacting protein mRNAs displayed higher expression levels in invasive lesions than in preinvasive lesions using samples obtained by laser capture microdissection (LCM) from transgenic erbB2, ras, and cyclin D1 mice. LCM-isolated tissues from patient-matched normal, ductal carcinoma in situ, and invasive ductal carcinoma revealed similar increased expression in invasive human cancers compared with preinvasive and normal samples. These genes induced anchorage independence, increased cell proliferation, and protected against apoptosis, singly or in collaboration with erbB2. Surprisingly, they were all up-regulated by 17B-estradiol and cyclin D1, and cyclin D1 overexpression increased p300/CBP binding to their promoters, supporting the model that cyclin D1-estrogen receptor (ER) coactivator interactions may be important to its role in ER-positive breast cancer. Additionally, an irreversible dual kinase inhibitor of ErbB signaling inhibited expression of the same genes. The up-regulation of genes contributing to increased invasiveness of ER-positive cancers offers a novel explanation for the contribution of cyclin D1 to a worse prognosis in ER-positive cancers. As targets of estrogen, cyclin D1, and erbB2 signaling, these candidates offer insights into the nature of the second events involved in breast cancer progression, regulatory events contributing to invasion, and potential targets of combined inhibition of hormone and growth factor signaling pathways. (Cancer Res 2006; 66(24): 11649-58)

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Baculovirus p35 and Z-VAD-fmk inhibit thapsigargin-induced apoptosis of breast cancer cells

Cited by 41 publications

References 24 publications

Etk/Bmx, a PH-domain containing tyrosine kinase, protects prostate cancer cells from apoptosis induced by photodynamic therapy or thapsigargin

Etk/Bmx, a PH-domain containing tyrosine kinase, protects prostate cancer cells from apoptosis induced by photodynamic therapy or thapsigargin

Calcium Is a Key Signaling Molecule in β-Lapachone-mediated Cell Death

Identification of Cyclin D1– and Estrogen-Regulated Genes Contributing to Breast Carcinogenesis and Progression

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