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Pancreatic cancer pkc

So Young Kim, Sojung Park, SeonA Yoo, Jin Kyung Rho, Eun Sung Jun, Suhwan Chang, Kyung Kon Kim, Song Cheol Kim, Inki Kim
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential biological anticancer agent. However, a wide range of human primary cancers, including pancreatic cancer, display resistance to apoptosis induction by TRAIL. Therefore, this resistance needs to be overcome to allow TRAIL to be successfully used in cancer therapy. In this study, we performed a compound screen to isolate TRAIL sensitizers and found that one of the identified compounds, 7-benzylidenenaltrexone maleate (BNTX), sensitized pancreatic cancer cells to TRAIL-induced apoptotic cell death...
May 12, 2017: Oncotarget
Suthakar Ganapathy, Bo Peng, Ling Shen, Tianqi Yu, Jean Lafontant, Ping Li, Rui Xiong, Alexandros Makriyannis, Changyan Chen
Gain of functional mutations in ras occurs in more than 30% of human malignancies and in particular 90% of pancreatic cancer. Mutant ras, via activating multiple effector pathways, not only promote cell growth or survival, but also apoptosis, depending upon cell types or circumstances. In order to further study the mechanisms of apoptosis induced by oncogenic ras, we employed the ras loop mutant genes and demonstrated that Akt functioned downstream of Ras in human pancreatic cancer or HPNE cells ectopically expressing mutated K-ras for the induction of apoptosis after the concurrent suppression of PKC α and β...
May 9, 2017: Oncotarget
Waldemar Wagner, Katarzyna D Kania, Wojciech M Ciszewski
Numerous G-protein coupled receptors have been reported to enhance cancer cell survival and resistance to clinically used chemotherapeutics. Recently, hydroxycarboxylic acid receptor 1 (HCAR1) was shown to drive lactate-dependent enhancement of cell survival and metastasis in pancreatic and breast cancers. Furthermore, our previous study confirmed the involvement of HCAR1 in lactate-related enhancement of DNA repair in cervical cancer cells. In the present study, we examined the possible mechanisms of HCAR1-mediated enhancement of DNA repair capacity...
February 20, 2017: DNA Repair
Akira Takasawa, Masaki Murata, Kumi Takasawa, Yusuke Ono, Makoto Osanai, Satoshi Tanaka, Masanori Nojima, Tsuyoshi Kono, Koichi Hirata, Takashi Kojima, Norimasa Sawada
Accumulating evidence has shown that dysregulation of tight junctions (TJs) is involved in tumor development and progression. In this study, we investigated the expression and subcellular distribution of tricellulin, which constitutes tricellular TJs, using human pancreatic adenocarcinomas. In well-differentiated pancreatic adenocarcinoma tissues, tricellulin immunostaining was prominent in the cytoplasm and the plasma membrane. In contrast, in poorly differentiated tissues, its immunostaining was predominantly observed in the nuclei and was almost absent in the plasma membrane...
2016: Scientific Reports
Yang Yu, Ling Tian, Xiao Feng, Jin Cheng, Yanping Gong, Xinjian Liu, Zhengxiang Zhang, Xuguang Yang, Sijia He, Chuan-Yuan Li, Qian Huang
Pancreatic cancer is a devastating disease characterized by treatment resistance and high recurrence rate. Repopulation of surviving tumor cells undergoing radiotherapy is one of the most common reasons for recurrence. Our previous studies have discovered a novel mechanism for repopulation after irradiation that activation of caspase-3 in irradiated tumor cells activates PKCδ/p38 axis to transmit proliferation signals promoting repopulation of surviving tumor cells. Here we found Sox2 expression is up-regulated in irradiated pancreatic cancer cells, which played a major role in tumor cell repopulation after irradiation...
May 28, 2016: Cancer Letters
Jami L Saloman, Kathryn M Albers, Dongjun Li, Douglas J Hartman, Howard C Crawford, Emily A Muha, Andrew D Rhim, Brian M Davis
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage...
March 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
Min Tao, Lu Liu, Meng Shen, Qiaoming Zhi, Fei-Ran Gong, Binhua P Zhou, Yadi Wu, Haiyan Liu, Kai Chen, Bairong Shen, Meng-Yao Wu, Liu-Mei Shou, Wei Li
Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo...
2016: Cell Cycle
Alok Kumar Mishra, Vinay Dubey, Asit Ranjan Ghosh
Obesity is one of the major challenges for public health in 21st century, with 1.9 billion people being considered as overweight and 600 million as obese. There are certain diseases such as type 2 diabetes, hypertension, cardiovascular disease, and several forms of cancer which were found to be associated with obesity. Therefore, understanding the key molecular mechanisms involved in the pathogenesis of obesity could be beneficial for the development of a therapeutic approach. Hormones such as ghrelin, glucagon like peptide 1 (GLP-1) peptide YY (PYY), pancreatic polypeptide (PP), cholecystokinin (CCK) secreted by an endocrine organ gut, have an intense impact on energy balance and maintenance of homeostasis by inducing satiety and meal termination...
January 2016: Metabolism: Clinical and Experimental
Man-Tzu Wang, Matthew Holderfield, Jacqueline Galeas, Reyno Delrosario, Minh D To, Allan Balmain, Frank McCormick
K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8. Restoring Fzd8 in K-Ras mutant pancreatic cells suppresses malignancy, whereas depletion of Fzd8 in H-Ras(V12)-transformed cells enhances their tumor initiating capacity...
November 19, 2015: Cell
Ana Santos Cravo, Edward Carter, Mert Erkan, Emma Harvey, Makoto Furutani-Seiki, Randall Mrsny
External adherens junction-based cell-cell contacts involving E-cadherin interactions function to sense planar cell status and modulate epithelial cell proliferation through Hippo (Hpo) and non-canonical Wnt pathways signaling. We hypothesized these regulatory processes should also be sensitive to a similar cell-cell contact sensor associated with apical-basal polarity events at epithelial surfaces. We used 2 human pancreatic cancer cell lines to explore this hypothesis: one with the capacity to form functional tight junction structures and polarize (HPAFII) and one lacking this capacity (AsPc1)...
July 2015: Tissue Barriers
Brittany L Carpenter, Min Chen, Teresa Knifley, Kelley A Davis, Susan M W Harrison, Rachel L Stewart, Kathleen L O'Connor
Integrin α6β4 is up-regulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion by altering the transcriptome. In this study, we found that integrin α6β4 up-regulates several genes in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (AREG), epiregulin (EREG), and ectodomain cleavage protease MMP1, which is mediated by promoter demethylation and NFAT5. The correlation of these genes with integrin α6β4 was confirmed in The Cancer Genome Atlas Pancreatic Cancer Database...
November 6, 2015: Journal of Biological Chemistry
Meng Shen, Meng-Yao Wu, Long-Pei Chen, Qiaoming Zhi, Fei-Ran Gong, Kai Chen, Dao-Ming Li, Yadi Wu, Min Tao, Wei Li
Cantharidin is an active constituent of mylabris, a traditional Chinese medicine, and is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in cell cycle control, apoptosis, and cell-fate determination. In the present study, we found that cantharidin repressed the invasive ability of pancreatic cancer cells and downregulated matrix metalloproteinase 2 (MMP2) expression through multiple pathways, including ERK, JNK, PKC, NF-κB, and β-catenin. Interestingly, transcriptional activity of the MMP2 promoter increased after treatment with PP2A inhibitors, suggesting the involvement of a posttranscriptional mechanism...
2015: Scientific Reports
Amanda M Butler, Michele L Scotti Buzhardt, Eda Erdogan, Shuhua Li, Kristin S Inman, Alan P Fields, Nicole R Murray
Pancreatic cancer is highly resistant to current chemotherapies. Identification of the critical signaling pathways that mediate pancreatic cancer transformed growth is necessary for the development of more effective therapeutic treatments. Recently, we demonstrated that protein kinase C iota (PKCι) and zeta (PKCζ) promote pancreatic cancer transformed growth and invasion, by activating Rac1→ERK and STAT3 signaling pathways, respectively. However, a key question is whether PKCι and PKCζ play redundant (or non-redundant) roles in pancreatic cancer cell transformed growth...
June 20, 2015: Oncotarget
Tetsuyuki Takahashi, Hisanori Uehara, Hirohisa Ogawa, Hitomi Umemoto, Yoshimi Bando, Keisuke Izumi
Associations between growth factor receptor-mediated cell signaling and cancer cell growth have been previously characterized. Receptors for prostaglandin E2, such as EP2, and EP4, play roles in cancer growth, progression and invasion. Thus, we examined the interactions between EP2/EP4- and IGF-1R-mediated cellular signaling in human pancreatic cancer cells. Selective antagonists against EP2 and EP4 abrogated IGF-1-stimulated cell growth and suppressed MEK/ERK phosphorylation. In subsequent experiments, phospho-antibody arrays indicated increased phosphorylation levels of protein kinase C-θ (PKC-θ) at the Thr538 position following the inhibition of EP2/EP4-mediated signaling...
March 10, 2015: Oncotarget
Xin Xie, Meng-Yao Wu, Liu-Mei Shou, Long-Pei Chen, Fei-Ran Gong, Kai Chen, Dao-Ming Li, Wei-Ming Duan, Yu-Feng Xie, Yi-Xiang Mao, Wei Li, Min Tao
Cantharidin is an active constituent of mylabris, a traditional Chinese therapeutic agent. Cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A). Cantharidin has been previously reported to efficiently repress the growth of pancreatic cancer cells. However, excessively activated protein kinase C (PKC) has been shown to improve cell survival following the adminstration of cantharidin. Tamoxifen is widely used in the treatment of estrogen receptor-positive breast cancer. In addition, an increasing number of studies have found that tamoxifen selectively inhibits PKC and represses growth in estrogen receptor-negative cancer cells...
February 2015: Oncology Letters
Peter Storz
In preclinical studies, protein kinase C (PKC) enzymes have been implicated in regulating many aspects of pancreatic cancer development and progression. However, clinical Phase I or Phase II trials with compounds targeting classical PKC isoforms were not successful. Recent studies implicate that mainly atypical and novel PKC enzymes regulate oncogenic signaling pathways in pancreatic cancer. Members of these two subgroups converge signaling induced by mutant Kras, growth factors and inflammatory cytokines. Different approaches for the development of inhibitors for atypical PKC and novel PKC have been described; and new compounds include allosteric inhibitors and inhibitors that block ATP binding...
April 2015: Expert Review of Anticancer Therapy
Yong Qin, Zhenhua Ma, Xiaoyan Dang, Wei Li, Qingyong Ma
We previously demonstrated that resveratrol (Res) regulates the expression of PKC α and δ, to eventually inhibit growth and induce apoptosis in human gastric cancer cells. In the present study, the effect of Res on the growth of human pancreatic cancer cells was investigated, to further unveil the underlying mechanism. The human pancreatic cancer cell line MIA PaCa-2 was treated with three different concentrations of Res. Cell proliferation was assessed by the MTT assay, and apoptosis was detected by flow cytometry...
November 2014: Molecular Medicine Reports
Jin Cheng, Ling Tian, Jingjing Ma, Yanping Gong, Zhengxiang Zhang, Zhiwei Chen, Bing Xu, Hui Xiong, Chuanyuan Li, Qian Huang
Pancreatic cancer is one of the most lethal human cancers, and radiotherapy is often implemented for locally advanced pancreatic ductal adenocarcinoma. Tumor cell repopulation is a major challenge in treating cancers after radiotherapy. In order to address the problem of tumor repopulation, our previous studies have demonstrated that dying cells stimulate the proliferation of living tumor cells after radiotherapy. In particular, dying cells undergoing apoptosis also activate survival or proliferation signals and release growth factors to surrounding living cells...
January 2015: Molecular Oncology
Eun Ji Lee, Mi Kyung Park, Hyun Ji Kim, June Hee Kang, You Ri Kim, Gyeoung Jin Kang, Hyun Jung Byun, Chang Hoon Lee
The stiffness of cancer cells is attributable to intermediate filaments such as keratin. Perinuclear reorganization via phosphorylation of specific serine residue in keratin is implicated in the deformability of metastatic cancer cells including the human pancreatic carcinoma cell line (PANC-1). 12-O-Tetradecanoylphorbol-13-acetate (TPA) is a potent tumor promoter and protein kinase C (PKC) activator. However, its effects on phosphorylation and reorganization of keratin 8 (K8) are not well known. Therefore, we examined the underlying mechanism and effect of TPA on K8 phosphorylation and reorganization...
February 2014: Biomolecules & Therapeutics
Tobias Forster, Vanessa Rausch, Yiyao Zhang, Orkhan Isayev, Katharina Heilmann, Frank Schoensiegel, Li Liu, Michelle Nessling, Karsten Richter, Sabrina Labsch, Clifford C Nwaeburu, Juergen Mattern, Jury Gladkich, Nathalia Giese, Jens Werner, Peter Schemmer, Wolfgang Gross, Martha M Gebhard, Clarissa Gerhauser, Michael Schaefer, Ingrid Herr
The extreme aggressiveness of pancreatic ductal adenocarcinoma (PDA) has been associated with blocked gap junctional intercellular communication (GJIC) and the presence of cancer stem cells (CSCs). We examined whether disturbed GJIC is responsible for a CSC phenotype in established and primary cancer cells and patient tissue of PDA using interdisciplinary methods based in physiology, cell and molecular biology, histology and epigenetics. Flux of fluorescent dyes and gemcitabine through gap junctions (GJs) was intact in less aggressive cells but not in highly malignant cells with morphological dysfunctional GJs...
March 30, 2014: Oncotarget
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