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Paclitaxel Enhances Tumoricidal Potential of TRAIL Via Inhibition of MAPK in Resistant Gastric Cancer Cells

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Paclitaxel Enhances Tumoricidal Potential of TRAIL Via Inhibition of MAPK in Resistant Gastric Cancer Cells ONCOLOGY REPORTS 35: 3009-3017, 2016 Paclitaxel enhances tumoricidal potential of TRAIL via inhibition of MAPK in resistant gastric cancer cells LIN LI1,2*, XIAN-ZI WEN1*, ZHAO-DE BU2, XIAO-JING CHENG1, XIAO-FANG XING1, XIAO-HONG WANG3, LIAN-HAI ZHANG2,3, TING GUO1, HONG DU1, YING HU3, BIAO FAN2 and JIA-FU JI1,2 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital and Institute, Beijing; Departments of 2Gastrointestinal Surgery and 3Tissue Bank, Peking University Cancer Hospital and Institute, Beijing, P.R. China Received November 21, 2015; Accepted January 7, 2016 DOI: 10.3892/or.2016.4666 Abstract. Tumor necrosis factor-related apoptosis-inducing Introduction ligand (TRAIL) holds promise for cancer therapy due to its unique capacity to selectively trigger apoptosis in cancer cells. Gastric cancer (GC) is the fourth most frequent malignancy However, TRAIL therapy is greatly hampered by its resistance. and the second leading cause of cancer mortality worldwide (1). A preclinical successful strategy is to identify combina- In China, most of the patients are identified at the advanced tion treatments that sensitize resistant cancers to TRAIL. In stage which leads to dismal prognosis. Radical surgery is the the present study, we fully assessed TRAIL sensitivity in 9 only curative therapy and chemotherapy serves as common gastric cancer cell lines. We found combined administration strategy for late stage patients. Patients with GC, however, are of paclitaxel (PTX) markedly enhanced TRAIL-induced not particularly sensitive to conventional chemotherapeutic apoptosis in resistant cancer cells both in vitro and in vivo. drugs. Thus, it is of great interest to find new approaches, and The sensitization to TRAIL was accompanied by activation targeted manipulation of apoptosis is a research hot spot (2). of mitochondrial apoptotic pathway, upregulation of TRAIL TRAIL, a member of tumor necrosis factor (TNF) super receptors and downregulation of anti-apoptotic proteins family, selectively triggers cell death in transformed cells while including C-IAP1, C-IAP2, Livin and Mcl-1. Noticeably, we causing virtually no toxic towards normal cells (3). TRAIL found PTX could suppress the activation of mitogen-activated initiates apoptotic signals via binding to two cell surface death protein kinases (MAPKs). Inhibition of MAPKs using specific receptors (DRs), DR4 (also known as TRAIL-R1) and DR5 inhibitors (ERK inhibitor U0126, JNK inhibitor SP600125 and (also known as TRAIL-R2), leading to receptor aggregation P38 inhibitor SB202190) facilitated TRAIL-mediated apop- and recruitment of Fas-associated death domain (FADD) tosis and cytotoxicity. Additionally, SP600125 upregulated followed by procaspase-8 (4). The apoptotic process then TRAL receptors as well as downregulated C-IAP2 and Mcl-1 follows two signaling pathways. In type I cells, activated suggesting the anti-apoptotic role of JNK. Thus, PTX-induced caspase-8 enables the autocatalytic cleavage of caspase suppression of MAPKs may contribute to restoring TRAIL cascade triggers apoptosis. While in type II cells, caspase-8 senstitivity. Collectively, our comprehensive analyses gave additionally triggers mitochondrial apoptosis pathway by new insight into the role of PTX on enhancing TRAIL sensi- activating cleavage of Bid, which induces the release of cyto- tivity, and provided theoretical references on the development chrome c from mitochondria and in turn activates caspase-9 to of combination treatment in TRAIL-resistant gastric cancer. finally execute cell death (5). Drugs targeting TRAIL pathway, including recombinant TRAIL and agonistic antibodies have been demonstrated with robust anticancer activity in a number of preclinical studies (6-8). Despite the attractive tumoricidal potential, TRAIL- based therapy is greatly hampered by its resistance, a major Correspondence to: Dr Biao Fan or Dr Jia-Fu Ji, Department of Gastrointestinal Surgery, Peking University Cancer Hospital and obstacle to clinical application (8-10). The most basic cause is Institute, 52 Fu-Cheng Road, Hai-Dian, Beijing 100142, P.R. China dysfunction of death receptors due to hyper-methylation (11), E-mail: [email protected] mutation (12) and loss of cell surface expression (13). The E-mail: [email protected] defects in caspase protein (14) and overexpression of pro- survival proteins, such as IAP family and anti-apoptotic *Contributed equally Bcl-2 family members (15-18), are also linked to TRAIL sensitivity. In addition, more recent findings suggested that Key words: Tumor necrosis factor-related apoptosis-inducing cell survival signals, including mitogen-activated protein ligand, paclitaxel, mitogen-activated protein kinase, gastric cancer, kinase (MAPK) pathway, phosphatidylinositol 3-kinase/Akt apoptosis, combination therapy pathway, and transcription factor NF-κB played pivotal roles in regulation of TRAIL signaling (19-22). Previous studies 3010 LI et al: TRAIL-SENSITIZING EFFECT OF PACLITAXEL demonstrated that TRAIL resistance could be alleviated or identified and measured by subtracting relative isotype control even reversed by combination therapy (23,24). PTX, one of values. the cytoskeletal drugs targeting tubulin, is commonly used in advanced GC treatment. It inhibits tumor cell proliferation Western blot assay. Total proteins were extracted using RIPA through stabilizing microtubule network and inhibiting micro- lysis buffer (Beijing Solarbio Science and Technology Co., tubule dynamics (25). PTX has been explored as sensitizing Ltd., Beijing, China) with protease inhibitors and phosphatase agent towards TRAIL in some cancer types (26-28), yet, the inhibitors (Beijing Solarbio Science and Technology). Protein molecular mechanisms were not fully elucidated. concentration was quantified using the Bradford method In the present study, we demonstrate that combined treat- (Pierce, Rockford, IL, USA). Equivalent amount of protein ment of PTX and TRAIL significantly boosted apoptosis (20 µg) was separated by 10% SDS-PAGE gels and transferred of TRAIL-resistant GC cells both in vitro and in vivo. The onto PVDF membranes (Millipore, Billerica, MA, USA). The molecular mechanisms underlying the synergism involved membranes were blocked in 5% non-fat milk in TBS-T for enhanced activation of caspases, upregulation of DRs and 1 h and incubated with primary antibodies overnight at 4˚C, downregulation of anti-apoptotic proteins. Moreover, we followed by incubation with HRP-conjugated secondary anti- present herein the inhibitory effect of MAPKs in TRAIL- bodies. Signals were detected using chemiluminescent agents induced apoptosis in GC and reveal for the first time that (Pierce). Primary antibodies of DR4 and GAPDH were from TRAIL-augmenting effect of PTX was partly due to suppres- Abcam (Cambridge, MA, USA), and DR5 was from Sigma- sion of the MAPK pathway. Aldrich (St. Louis, MO, USA). Other primary antibodies purchased from Cell Signaling Technology (Danvers, MA, Materials and methods USA) were as follows: caspase-3 (#9662), cleaved-caspase-3 (#9664), caspase-7 (#9492), cleaved-caspase-7 (#8438), Cell culture and reagents. GC cell lines AGS, NCI-N87, SNU-1 caspase-8 (#9746), caspase-9 (#9502), cleaved-caspase-9 and SNU-16 were purchased from the American Type Culture (#7237), PARP (#9542), cleaved-PARP (#5625), Bid (#2002), Collection (ATCC; Manassas, VA, USA). MKN28 and NUGC3 C-IAP1 (#7065), C-IAP2 (#3130), XIAP (#2045), Livin (#5471), were purchased from Health Science Research Resources Bank Bcl-xL (#2764), Bcl-2 (#2870), Mcl-1 (#5453), ERK (#4695), (Tokyo, Japan), and SGC-7901, BGC-823 and MGC-803 were phosphorylated-ERK (#4370), JNK (#9258), phosphorylated- obtained from Cell Research Institute (Shanghai, China). All JNK (#4668), p38 (#8690), phosphorylated-p38 (#4511). cells were maintained in Dulbecco's modified Eagle's medium (DMEM; Gibco-BRL, Carlsbad, CA, USA) containing 10% siRNA transfection. C-IAP1 siRNA and scrambled siRNA fetal bovine serum (FBS) and penicillin/streptomycin at 37˚C were purchased from Santa Cruz Biotechnology (Santa Cruz, 5 with 5% CO2. Recombinant human TRAIL was purchased CA, USA). Cells (1x10 ) in 6-well plates were incubated from PeproTech EC Ltd. (London, UK). The small molecule for 24 h and then transfected with siRNA (100 nmol/l) and inhibitors U0126 (#S1102), SP600125 (#S1460) and SB202190 Lipofectamine 2000 reagent (Invitrogen, Carlsbad, CA, USA) (#S1077) were obtained from Selleck Chemicals (Houston, in Opti-MEM without serum, according to the manufacturer's TX, USA). The chemotherapeutic drug PTX was from Beijing specifications. After 6 h, the medium was replaced with fresh Union Pharmaceutical Factory (Beijing, China). medium. Forty-eight hours after transfection, C-IAP1 knock- down effect was verified by western blotting. Cell viability assay. Cell viability was assessed using Cell Counting kit-8 assay (CCK-8) (Dojindo Molecular In vivo xenograft study. Animal studies were carried out in Technologies, Kumamoto, Japan). Briefly, cells were seeded strict adherence with institutional guidelines. SGC-7901 cells onto 96-well plates at a density of 3-5x103 cells/well and (2x106/200 µl per mouse) were subcutaneously injected into allowed to attach for 24 h. The cells were incubated with the right hind legs of 6-8 week-old female nude mice. When indicated concentrations of TRAIL and/or PTX for 24 h. tumors volume reached 50-100 mm3, the
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