Antiandrogen-induced cell death in LNCaP human prostate cancer cells

Lee, E C Y; Zhan, Ping; Schallhom, R; Packman, Kathryn; Tenniswood, Martin

doi:10.1038/sj.cdd.4401228

Cited by 54 publications

(46 citation statements)

References 42 publications

(43 reference statements)

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“…5 There is emerging evidence to show that bicalutamide exerts its proapoptotic effects independent of mitochondrial membrane changes and that a by-product of caspase 8 is produced as a result of caspase 3 action. 13 Paradoxically, there is evidence to suggest that bicalutamide in advanced disease may be agonistic in nature. Some authors have reported that bicalutamide works as an agonist in cells derived from prolonged periods of androgen ablation, leading to an androgenindependent (LNCaP-abl) cell line.…”

Section: Discussionmentioning

confidence: 99%

Differential mechanisms of bicalutamide-induced apoptosis in prostate cell lines

Floyd

Teahan

Fitzpatrick

et al. 2008

Prostate Cancer Prostatic Dis

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Bicalutamide is a non-steroidal antiandrogen used in the treatment of prostate cancer. Although widely accepted as an androgen receptor antagonist, the mechanism by which it induces apoptosis remains unclear. Defining exact pathways by which bicalutamide induces its apoptotic effects would help to advance its clinical applications. We aimed to (a) examine the apoptotic effects of bicalutamide at 24 h and (b) comment on the role of the caspases and calpains in mediating bicalutamide-induced apoptosis in androgen-dependent and androgen-independent cells. PWR-1E, PC-3 and DU-145 cells were treated with bicalutamide and assessed for apoptosis by flow cytometry at 24 h. DU-145 cells were used to compare differences between two different metastatic receptor-negative cells and to verify apoptotic induction at 48 h. To delineate a specific pathway of action for bicalutamide, PC-3 and PWR-1E cells were pretreated with specific inhibitors of caspasedependent (zVAD-FMK) and caspase-independent pathways (calpain 2 inhibitor). Bicalutamide induced apoptosis in androgen-dependent PWR-1E cells via a caspase-dependent and calpainindependent mechanism. In androgen-independent PC-3 cells, bicalutamide also induced apoptosis by mechanisms that were partially inhibited by pan-caspase inhibition but were partially calpain dependent. Understanding into how bicalutamide exerts its effects in androgenindependent cells will yield further insights into the treatment of hormone-refractory disease.

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Section: Discussionmentioning

confidence: 99%

Differential mechanisms of bicalutamide-induced apoptosis in prostate cell lines

Floyd

Teahan

Fitzpatrick

et al. 2008

Prostate Cancer Prostatic Dis

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“…[1][2][3] It is well demonstrated that castration in rodent models or androgen ablation in cell culture system causes a rapid apoptotic response in the prostate-derived epithelial cells. 4,5 Based on these phenomena, androgen ablation therapy has been used in clinical management of prostate cancer patients. 6 However, the disease progresses to a more aggressive androgen-independent stage (termed 'hormonerefractory' because the tumor is resistant to androgen ablation therapy).…”

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confidence: 99%

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

et al. 2007

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Androgen receptor (AR) is a critical factor in the development and progression of prostate cancer. We and others recently demonstrated that eliminating AR expression leads to apoptotic cell death in AR-positive prostate cancer cells. To understand the mechanisms of AR-dependent survival, we performed a genome-wide search for AR-regulated survival genes. We found that serum/glucocorticoid-induced protein kinase-1 (SGK-1) mRNA levels were significantly upregulated after androgen stimulation, which was confirmed to be AR dependent. Promoter analysis revealed that the AR interacted with the proximal and distal regions of the sgk1 promoter, leading to sgk-1 promoter activation after androgen stimulation. Functional assays demonstrated that SGK-1 was indispensable for the protective effect of androgens on cell death induced by serum starvation. SGK-1 overexpression not only rescued cells from AR small-interfering RNA (siRNA)-induced apoptosis, but also enhanced AR transactivation, even in the absence of androgen. Additionally, SGK-1 siRNA reduced AR transactivation, indicating a positive feedback effect of SGK-1 expression on AR-mediated gene expression and cellular survival. Taken together, our data suggest that SGK-1 is an androgen-regulated gene that plays a pivotal role in AR-dependent survival and gene expression.

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“…By targeting AR, WT-ANXA7 represented a potential alternative to antiandrogens which may promote tumor invasiveness. 45 Because of the gain of function, AR becomes an oncogene in type-II androgen depletion insensitive cells, but not in the type-I DU145 and PC3. In fact, RB1 can activate AR-dependent apoptosis, 8,21 and the reinforced AR can still function as a tumor suppressor in PC3 cells.…”

Section: Discussionmentioning

confidence: 99%

Annexin‐A7 protects normal prostate cells and induces distinct patterns of RB‐associated cytotoxicity in androgen‐sensitive and ‐resistant prostate cancer cells

Torosyan

Šimáková

Shanmugam

et al. 2009

Intl Journal of Cancer

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The tumor suppressor role of annexin-A7 (ANXA7) was previously demonstrated by cancer susceptibility in Anxa7(1/2)-mice and by ANXA7 loss in human cancers, especially in hormone-resistant prostate tumors. To gain mechanistic insights into ANXA7 tumor suppression, we undertook an in vitro study in which we compared wild-type (WT)-ANXA7 and dominant-negative (DN)-ANXA7 effects to a conventional tumor suppressor p53 in prostate cancer cells with different androgen sensitivity. Unlike p53 (which caused cell growth arrest and apoptosis to a noticeable extent in benign PrEC), WT-ANXA7 demonstrated profound cytotoxicity in androgen-sensitive LNCaP as well as in the androgen-resistant DU145 and PC3 prostate cancer cells, but not in PrEC. In androgen-sensitive LNCaP, WT-ANXA7 decreased lowmolecular-weight (LMW) AR protein forms and maintained higher retinoblastoma 1 (RB1)/phospho-RB1 ratio. In contrast, DN-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) increased LMW-AR forms and hyperphosphorylated RB1 that was consistent with the lack of DN-ANXA7 cytotoxicity. According to the microarray-based Ingenuity Pathways Analysis, a major WT-ANXA7 effect in androgen-sensitive LNCaP constituted of upregulation of the RB1-binding transcription factor E2F1 along with its downstream proapoptotic targets such as ASK1 and ASPP2. These results suggested a reversal of the RBdependent repression of the proapoptotic E2F-mediated transcription. However, DN-ANXA7 increased RB1/2 (but not E2F1) expression and induced the proliferation-promoting ERK5, thereby maintaining the RB-dependent repression of E2F-mediated apoptosis in LNcaP. On the other hand, in androgen-resistant cells, WT-ANXA7 tumor suppressor effects involved PTEN and NFkB pathways. Thus, ANXA7 revived the RB-associated cell survival control and overcame androgen resistance and dysfunctional status of major tumor suppressors commonly mutated in prostate cancer. Published 2009 UICC. This article is a US Government work and, as such, is in the public domain in the United States of America.Key words: annexin-A7 vs. p53; RB-E2F; AR; prostate cancer; Ingenuity Pathways Analysis Annexin-VII (ANXA7 or synexin) is a ubiquitously expressed member of the multifunctional Ca/phospholipid-binding annexin family. In addition to Ca 21 -activated GTPase activity as well as involvement in membrane fusion and exocytosis, ANXA7 demonstrated tumor suppressor function in murine model 1 and in human prostate and breast cancers. 2,3 Our large-scale study on ANXA7 protein expression in different cancers 4 identified a drastic ANXA7 loss in the hormone-refractory prostate cancers as well as an abundant ANXA7 presence in the adrenal gland, a major source of sex hormone precursors. Although tumor suppressor mechanisms of ANXA7 are not yet elucidated, these data suggested that ANXA7, which has androgen-receptor (AR) regulatory elements in its promoter, may be involved in the regulation of androgen-dependent cell survival in prostate cancer cells.Androgen-dependent proliferation is p...

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Antiandrogen-induced cell death in LNCaP human prostate cancer cells

Cited by 54 publications

References 42 publications

Differential mechanisms of bicalutamide-induced apoptosis in prostate cell lines

Differential mechanisms of bicalutamide-induced apoptosis in prostate cell lines

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

Annexin‐A7 protects normal prostate cells and induces distinct patterns of RB‐associated cytotoxicity in androgen‐sensitive and ‐resistant prostate cancer cells

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