c-Jun NH2-terminal kinase-induced proteasomal degradation of c-FLIPL/S and Bcl2 sensitize prostate cancer cells to Fas- and mitochondria-mediated apoptosis by tetrandrine

doi:10.1016/j.bcp.2014.08.014

Biochemical Pharmacology

Volume 91, Issue 4, 15 October 2014, Pages 457-473

https://doi.org/10.1016/j.bcp.2014.08.014 Get rights and content

Abstract

Tetrandrine, a constituent of Chinese herb Stephania tetrandra, causes cell death in prostate cancer, but the molecular mechanisms leading to apoptosis is not known. Here we demonstrated that tetrandrine selectively inhibits the growth of prostate cancer PC3 and DU145 cells compared to normal prostate epithelial PWR-1E cells. Tetrandrine-induced cell death in prostate cancer cells is caused by reactive oxygen species (ROS)-mediated activation of c-Jun NH₂-terminal kinase (JNK1/2). JNK1/2-mediated proteasomal degradation of c-FLIP_L/S and Bcl₂ proteins are key events in the sensitization of prostate cancer cells to Fas- and mitochondria-mediated apoptosis by tetrandrine. Tetrandrine-induced JNK1/2 activation caused the translocation of Bax to mitochondria by disrupting its association with Bcl₂ which was accompanied by collapse of mitochondrial membrane potential (MMP), cytosolic release of cytochrome c and Smac, and apoptotic cell death. Additionally, tetrandrine-induced JNK1/2 activation increased the phosphorylation of Bcl₂ at Ser70 and facilitated its degradation via the ubiquitin-mediated proteasomal pathway. In parallel, tetrandrine-mediated ROS generation also caused the induction of ligand-independent Fas-mediated apoptosis by activating procaspase-8 and Bid cleavage. Inhibition of procaspase-8 activation attenuated the cleavage of Bid, loss of MMP and caspase-3 activation suggest that tetrandrine-induced Fas-mediated apoptosis is associated with the mitochondrial pathway. Furthermore, most of the signaling effects of tetrandrine on apoptosis were significantly attenuated in the presence of antioxidant N-acetyl-l-cysteine, thereby confirming the involvement of ROS in these events. In conclusion, the results of the present study indicate that tetrandrine-induced apoptosis in prostate cancer cells is initiated by ROS generation and that both intrinsic and extrinsic pathway contributes to cell death.

Graphical abstract

Introduction

Prostate cancer is one of the most prevalent malignancies affecting men of all ages worldwide and is the second leading cause of cancer-related death in American men [1]. Prostate cancer development is initially androgen dependent, so the basic therapeutic strategy has been the deprivation of androgen [2]. Although most patients initially respond to androgen deprivation therapy by showing low prostate-specific antigen values, they invariably relapse with a more aggressive form of prostate cancer termed androgen-independent or castration-resistant prostate cancer (CRPC) [3], [4]. Yet, the molecular mechanisms that promote the development of CRPC are not fully understood. Prostate tumors that recur after androgen deprivation therapy have been shown to have amplified androgen receptor gene, resulting in increased androgen receptor expression and hypersensitivity to low levels of circulating androgens [5], [6], [7]. Certain growth factors such as epidermal growth factor and insulin-like growth factor-I have been shown to activate androgen receptor in the absence of androgen [8]. Overexpression of antiapoptotic proteins such as Bcl₂ and c-FLIP are seen in CRPC, which have been implicated in promoting tumor survival and reducing sensitivity to chemotherapy [9], [10]. Currently there is no effective therapy for CRPC and the median survival after the development of CRPC is 20–24 months [11], [12]. The CRPC is an invariably lethal condition, which frequently metastasize and is associated with a significant morbidity and mortality. Therefore, identification of agents that will selectively kill or sensitize castration-resistant tumor cells with no additional toxicity to normal tissues would have significant impact on existing therapies.

Tetrandrine, a benzylisoquinoline alkaloid, is a calcium channel blocker isolated from the Chinese herb Stephania tetrandra S. Moore [13], [14], [15]. Tetrandrine is used in traditional Chinese medicine as an antirheumatic, anti-inflammatory, and antihypertensive agent for the past several years [16], [17], [18], [19]. Tetrandrine has been used as an antifibrotic drug to treat the lesions of silicosis in China since the 1960s. Tetrandrine has been shown to be a potent inhibitor of P-glycoprotein drug efflux [20], [21], [22]. Compared to verapamil, etoposide and cytarabine, tetrandrine was more effective in reversing drug resistance to daunorubicin, vinblastine and doxorubicin in leukemia cells [21], [22]. Tetrandrine exerts cytotoxic effect by inhibiting cell proliferation and inducing apoptosis in various cancer cells including breast cancer, lung cancer, hepatoma, glioma, leukemia and colon cancer [23], [24], [25], [26], [27], [28], [29]. In addition, tetrandrine modulates many cellular signaling events, including cell cycle arrest, mitogen-activated protein kinase activation, NF-κB signaling, Wnt/β-catenin signaling, and the transforming growth factor-β signaling pathway [24], [27], [28], [30], [31], [32]. Recent studies have indicated that tetrandrine used alone can exhibit significant anti-cancer activity against cancer cells by inhibiting pathways involved in cell proliferation, migration and angiogenesis [26], [28]. Despite its potential as an anti-cancer agent, the effects of tetrandrine on prostate cancer have not been studied. In the present study, we elucidate the mechanism through which tetrandrine induces proapoptotic effect in androgen-independent prostate cancer PC3 and DU145 cells. The results of these studies show that tetrandrine-induced apoptosis in prostate cancer cells is dependent on reactive oxygen species (ROS) generation and that contributes to cell death. Furthermore, we demonstrate for the first time that ROS-mediated activation of JNK1/2 leads to ubiquitin-mediated proteasomal degradation of c-FLIP_L/S and Bcl₂, and sensitize prostate cancer cells to Fas- and mitochondria-mediated apoptosis by tetrandrine.

Section snippets

Cell lines and culture conditions

Human prostate carcinoma cell lines, PC3 and DU145, and the normal epithelial prostate cell line, PWR-1E, were obtained from the American Type Culture Collection (Rockville, MD). The prostate cancer cell lines were cultured in RPMI-1640 (Hyclone, Logan, UT) supplemented with 10% fetal bovine serum (Invitrogen, Carlsbad, CA), 50 mg/ml penicillin and 50 mg/ml streptomycin (Invitrogen, Carlsbad, CA), and maintained in an incubator with a humidified atmosphere of 95% air and 5% CO₂ at 37 °C. The

Tetrandrine causes apoptosis in prostate cancer cells

The antiproliferative effects of tetrandrine on prostate cancer cell lines, PC3 and DU145, and normal prostate epithelial cell line, PWR-1E cells, were determined by an MTT assay [33]. Results presented in Fig. 1 showed that at concentrations ranging from 0 to 80 μM, tetrandrine gradually decreased the viability of PC3 (Fig. 1A), DU145 (Fig. 1B) and PWR-1E (Fig. 1C) cells in a dose- and time-dependent manner. The results of MTT assay showed that PWR-1E cells were more resistant to tetrandrine

Discussion

The pharmacologic action of tetrandrine has gathered increased attention in recent years in view of its potential as a novel anti-cancer drug either alone or in combination with generic drugs [13], [14], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. Previous studies have shown that tetrandrine causes cell cycle arrest and apoptosis in cancer cell lines of different tissue origins in vitro and in some tumor xenograft models in vivo, and modulates many genes and proteins involved in

Conflict of interest

The authors state no conflict of interest.

Acknowledgement

This work was supported by National Institutes of Health Grant 1P20 MD006882.

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c-Jun NH2-terminal kinase-induced proteasomal degradation of c-FLIPL/S and Bcl2 sensitize prostate cancer cells to Fas- and mitochondria-mediated apoptosis by tetrandrine

Abstract

Graphical abstract

Introduction

Section snippets

Cell lines and culture conditions

Tetrandrine causes apoptosis in prostate cancer cells

Discussion

Conflict of interest

Acknowledgement

Trends Pharmacol Sci

J Biol Chem

Biochem Pharmacol

J Biol Chem

Leuk Res

Eur J Cancer

Biochem Pharmacol

J Immunol Methods

J Biol Chem

J Biol Chem

Biochim Biophys Acta

Mol Cell

J Biol Chem

Methods Enzymol

J Biol Chem

Biochim Biophys Acta

Cell

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Pharmacol

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Cancer statistics, 2010

CA Cancer J Clin

Endocrine treatment in prostate cancer

Semin Surg Oncol

The role of androgen in the regulation of programmed cell death/apoptosis in normal and malignant prostatic tissue

Semin Cancer Biol

Minireview: alternative activation pathways for the androgen receptor in prostate cancer

Mol Endocrinol

In vivo amplification of the androgen receptor gene and progression of human prostate cancer

Nat Genet

Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer

Cancer Res

Castration-resistant prostate cancer: descriptive yet pejorative?

J Clin Oncol

Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor

Cancer Res

Detection of the apoptosis-suppressing oncoprotein bcl-2 in hormone-refractory human prostate cancers

Am J Pathol

Elevation of c-FLIP in castrate-resistant prostate cancer antagonizes therapeutic response to androgen receptor-targeted therapy

Clin Cancer Res

c-Jun NH₂-terminal kinase-induced proteasomal degradation of c-FLIP_L/S and Bcl₂ sensitize prostate cancer cells to Fas- and mitochondria-mediated apoptosis by tetrandrine