Paclitaxel enhances tumoricidal potential of TRAIL via inhibition of MAPK in resistant gastric cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promise for cancer therapy due to its unique capacity to selectively trigger apoptosis in cancer cells. However, TRAIL therapy is greatly hampered by its resistance. A preclinical successful strategy is to identify combination treatments that sensitize resistant cancers to TRAIL. In the present study, we fully assessed TRAIL sensitivity in 9 gastric cancer cell lines. We found combined administration of paclitaxel (PTX) markedly enhanced TRAIL-induced apoptosis in resistant cancer cells both in vitro and in vivo. The sensitization to TRAIL was accompanied by activation of mitochondrial apoptotic pathway, upregulation of TRAIL receptors and downregulation of anti-apoptotic proteins including C-IAP1, C-IAP2, Livin and Mcl-1. Noticeably, we found PTX could suppress the activation of mitogen-activated protein kinases (MAPKs). Inhibition of MAPKs using specific inhibitors (ERK inhibitor U0126, JNK inhibitor SP600125 and P38 inhibitor SB202190) facilitated TRAIL-mediated apoptosis and cytotoxicity. Additionally, SP600125 upregulated TRAL receptors as well as downregulated C-IAP2 and Mcl-1 suggesting the anti-apoptotic role of JNK. Thus, PTX-induced suppression of MAPKs may contribute to restoring TRAIL senstitivity. Collectively, our comprehensive analyses gave new insight into the role of PTX on enhancing TRAIL sensitivity, and provided theoretical references on the development of combination treatment in TRAIL-resistant gastric cancer.

[1]  S. Eo,et al.  Inhibition of the autophagy flux by gingerol enhances TRAIL-induced tumor cell death. , 2015, Oncology reports.

[2]  Jun Liang,et al.  Downregulation of SNAIL sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis by regulating the NF-κB pathway. , 2015, Oncology reports.

[3]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[4]  C. Duckett,et al.  Effects of Physiological and Synthetic IAP Antagonism on c-IAP-Dependent Signaling , 2015, Oncogene.

[5]  B. Aggarwal,et al.  Targeting death receptors for TRAIL by agents designed by Mother Nature. , 2014, Trends in pharmacological sciences.

[6]  Rachana Trivedi,et al.  Medicarpin, a legume phytoalexin sensitizes myeloid leukemia cells to TRAIL-induced apoptosis through the induction of DR5 and activation of the ROS-JNK-CHOP pathway , 2014, Cell Death and Disease.

[7]  Hyung Gyun Kim,et al.  Ilimaquinone induces death receptor expression and sensitizes human colon cancer cells to TRAIL-induced apoptosis through activation of ROS-ERK/p38 MAPK-CHOP signaling pathways. , 2014, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[8]  Chi-Tang Ho,et al.  CCT327 enhances TRAIL-induced apoptosis through the induction of death receptors and downregulation of cell survival proteins in TRAIL-resistant human leukemia cells. , 2014, Oncology reports.

[9]  Kazuhiro Yoshida,et al.  Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. , 2014, The Lancet. Oncology.

[10]  K. Strebhardt,et al.  pERK 1/2 inhibit Caspase‐8 induced apoptosis in cancer cells by phosphorylating it in a cell cycle specific manner , 2014, Molecular oncology.

[11]  John Calvin Reed,et al.  Small-Molecule IAP Antagonists Sensitize Cancer Cells to TRAIL-Induced Apoptosis: Roles of XIAP and cIAPs , 2013, Molecular Cancer Therapeutics.

[12]  E. Y. Kim,et al.  CAPE promotes TRAIL-induced apoptosis through the upregulation of TRAIL receptors via activation of p38 and suppression of JNK in SK-Hep1 hepatocellular carcinoma cells. , 2013, International journal of oncology.

[13]  J. Cheong,et al.  Cordycepin increases sensitivity of Hep3B human hepatocellular carcinoma cells to TRAIL-mediated apoptosis by inactivating the JNK signaling pathway. , 2013, Oncology reports.

[14]  H. Ford,et al.  On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics , 2013, Oncogene.

[15]  Rebecca C Fitzgerald,et al.  A systematic approach to therapeutic target selection in oesophago-gastric cancer , 2012, Gut.

[16]  A. López-Rivas,et al.  Control of FLIPL expression and TRAIL resistance by the extracellular signal-regulated kinase1/2 pathway in breast epithelial cells , 2012, Cell Death and Differentiation.

[17]  P. Sorger,et al.  Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks , 2012, Cell.

[18]  S. Antonia,et al.  Paclitaxel and TRAIL synergize to kill paclitaxel-resistant small cell lung cancer cells through a caspase-independent mechanism mediated through AIF. , 2011, Anticancer research.

[19]  R. Herbst,et al.  Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Ye Zhang,et al.  Phosphoinositide 3-kinase/Akt and nuclear factor κB pathways are involved in tumor necrosis factor-related apoptosis-inducing ligand resistance in human gastric cancer cells. , 2010, Molecular medicine reports.

[21]  E. Smit,et al.  Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and bevacizumab in patients with advanced non-squamous non-small-cell lung cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  J. Wiezorek,et al.  Death Receptor Agonists as a Targeted Therapy for Cancer , 2010, Clinical Cancer Research.

[23]  W. Thasler,et al.  JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand , 2008, Gut.

[24]  Baolin Zhang,et al.  TRAIL Resistance of Breast Cancer Cells Is Associated with Constitutive Endocytosis of Death Receptors 4 and 5 , 2008, Molecular Cancer Research.

[25]  D. Camidge,et al.  Targeted manipulation of apoptosis in cancer treatment. , 2008, The Lancet. Oncology.

[26]  A. Thorburn,et al.  Tumor-derived Mutations in the TRAIL Receptor DR5 Inhibit TRAIL Signaling through the DR4 Receptor by Competing for Ligand Binding* , 2007, Journal of Biological Chemistry.

[27]  K. Flaherty,et al.  Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. , 2007, Cancer cell.

[28]  L. Broemeling,et al.  Novel in vivo imaging shows up-regulation of death receptors by paclitaxel and correlates with enhanced antitumor effects of receptor agonist antibodies , 2006, Molecular Cancer Therapeutics.

[29]  K. Schulze-Osthoff,et al.  Loss of Caspase-9 Provides Genetic Evidence for the Type I/II Concept of CD95-mediated Apoptosis* , 2006, Journal of Biological Chemistry.

[30]  R. Zeillinger,et al.  Contribution of Epigenetic Silencing of Tumor Necrosis Factor–Related Apoptosis Inducing Ligand Receptor 1 (DR4) to TRAIL Resistance and Ovarian Cancer , 2005, Molecular Cancer Research.

[31]  E. Pasquier,et al.  Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway. , 2004, Molecular cancer therapeutics.

[32]  B. Dörken,et al.  Paclitaxel-induced apoptosis in BJAB cells proceeds via a death receptor-independent, caspases-3/-8-driven mitochondrial amplification loop , 2003, Oncogene.

[33]  J. Eriksson,et al.  Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling in Activated T Cells Abrogates TRAIL-Induced Apoptosis Upstream of the Mitochondrial Amplification Loop and Caspase-81 , 2002, The Journal of Immunology.

[34]  S. Horwitz,et al.  Selective potentiation of paclitaxel (taxol)-induced cell death by mitogen-activated protein kinase kinase inhibition in human cancer cell lines. , 2001, Molecular pharmacology.

[35]  T. McDonnell,et al.  TRAIL (APO-2L) induces apoptosis in human prostate cancer cells that is inhibitable by Bcl-2 , 2001, Oncogene.

[36]  A. Eggert,et al.  Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression , 2000, Oncogene.

[37]  D. Lawrence,et al.  Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. , 2000, Immunity.

[38]  S. Marsters,et al.  Induction of Apoptosis by Apo-2 Ligand, a New Member of the Tumor Necrosis Factor Cytokine Family* , 1996, The Journal of Biological Chemistry.

[39]  S. Kuo,et al.  CCT 327 enhances TRAIL-induced apoptosis through the induction of death receptors and downregulation of cell survival proteins in TRAIL-resistant human leukemia cells , 2014 .

[40]  K. Bhalla,et al.  Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. , 2001, Cancer research.