Transcription factor Sp1 is upregulated by PKCι to drive the expression of YAP1 during pancreatic carcinogenesis

2020 ◽  
Author(s):  
Jinhe Yang ◽  
Junli Wang ◽  
Hongmei Zhang ◽  
Changlong Li ◽  
Changyan Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Pancreatic Tumors ◽  
Antitumor Effects ◽  
Pancreatic Cancer Cells ◽  
Factor Specificity ◽  
Underlying Mechanisms ◽  
Specificity Protein

Abstract Recently, we identified that the atypical protein kinase C isoform ι (PKCι) enhances the expression of YAP1 to promote the tumorigenesis of pancreatic adenocarcinoma harboring mutant KRAS (mu-KRAS). To advance our understanding about underlying mechanisms, we analyze the transcription of YAP1 in pancreatic cancer cells and reveal that transcription factor Specificity Protein 1 (Sp1) is upregulated by PKCι and subsequently binds to multiple sites in YAP1 promoter to drive the transactivation of YAP1 in pancreatic cancer cells carrying mu-KRAS. The bioinformatics analysis further substantiates that the expression of PKCι, Sp1 and YAP1 is correlated and associated with the stages and prognosis of pancreatic tumors. Moreover, our apoptotic detection data demonstrate that combination of PKCι and Sp1 inhibitors at subtoxic doses displays synergistic effects on inducing apoptosis and reversing the immunosuppression of pancreatic cancer cells, establishing the combination of PKCι and Sp1 inhibitors as a promising novel therapeutic approach, or an adjuvant strategy to potentiate the antitumor effects of other immunotherapeutic agents in pancreatic cancer treatment.

scholarly journals Mechanical stress in pancreatic cancer: Signaling pathway adaptation activates cytoskeletal remodeling and enhances cell migration

2021 ◽  
Author(s):  
Maria Kalli ◽  
Ruxuan Li ◽  
Gordon B Mills ◽  
Triantafyllos Stylianopoulos ◽  
Ioannis K Zervantonakis
Keyword(s):  
Pancreatic Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Mechanical Stress ◽  
Large Scale ◽  
Metastatic Potential ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Novel Approach ◽  
Underlying Mechanisms

New treatments for patients with advanced or metastatic pancreatic cancers are urgently needed due to their resistance to all current therapies. Current studies focus on alternative treatment approaches that target or normalize the abnormal microenvironment of pancreatic tumors, which among others, is responsible for elevated mechanical stress in the tumor interior. Nevertheless, the underlying mechanisms by which mechanical stress regulates pancreatic cancer metastatic potential remain elusive. Herein, we used a large-scale proteomic assay to profile mechanical stress-induced signaling cascades that drive the motility of pancreatic cancer cells. Proteomic analysis, together with selective protein inhibition and siRNA treatments, revealed that mechanical stress enhances cell migration through activation of the p38 MAPK/HSP27 and JNK/c-Jun signaling axes, and activation of the actin cytoskeleton remodelers: Rac1, cdc42, and Myosin II. Our results highlight targeting aberrant signaling in cancer cells that are adapted to the mechanical tumor microenvironment as a novel approach to effectively limit pancreatic cancer cell migration.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

2020 ◽  
Vol 48 (04) ◽  
pp. 1005-1019
Author(s):  
Lijuan Hu ◽  
Xijuan Chen ◽  
Shuai Qiu ◽  
Jing Yang ◽  
Hongyi Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Insulin ◽  
Igf1r Expression ◽  
Expression And Activity

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

Bufalin exerts antitumor effects by inducing cell cycle arrest and triggering apoptosis in pancreatic cancer cells

Tumor Biology ◽  
2013 ◽  
Vol 35 (3) ◽  
pp. 2461-2471 ◽  
Author(s):  
Meiying Li ◽  
Xuejun Yu ◽  
Hui Guo ◽  
Limei Sun ◽  
Aijun Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Antitumor Effects ◽  
Cycle Arrest ◽  
Pancreatic Cancer Cells

scholarly journals A G-Quadruplex-Binding Small Molecule and the HDAC Inhibitor SAHA (Vorinostat) Act Synergistically in Gemcitabine-Sensitive and Resistant Pancreatic Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5407
Author(s):  
Ahmed Abdullah Ahmed ◽  
Stephen Neidle
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Hdac Inhibitor ◽  
Synergistic Effects ◽  
Immunoblot Analysis ◽  
Strand Break ◽  
Torsional Strain ◽  
Pancreatic Cancer Cells ◽  
Naphthalene Diimide

The stabilisation of G-quadruplexes (G4s) by small-molecule compounds is an effective approach for causing cell growth arrest, followed by cell death. Some of these compounds are currently being developed for the treatment of human cancers. We have previously developed a substituted naphthalene diimide G4-binding molecule (CM03) with selective potency for pancreatic cancer cells, including gemcitabine-resistant cells. We report here that CM03 and the histone deacetylase (HDAC) inhibitor SAHA (suberanilohydroxamic acid) have synergistic effects at concentrations close to and below their individual GI50 values, in both gemcitabine-sensitive and resistant pancreatic cancer cell lines. Immunoblot analysis showed elevated levels of γ-H2AX and cleaved PARP proteins upon drug combination treatment, indicating increased levels of DNA damage (double-strand break events: DSBs) and apoptosis induction, respectively. We propose that the mechanism of synergy involves SAHA relaxing condensed chromatin, resulting in higher levels of G4 formation. In turn, CM03 can stabilise a greater number of G4s, leading to the downregulation of more G4-containing genes as well as a higher incidence of DSBs due to torsional strain on DNA and chromatin structure.

Rottlerin suppresses growth of human pancreatic tumors in nude mice, and pancreatic cancer cells isolated from KrasG12D mice

2014 ◽  
Vol 353 (1) ◽  
pp. 32-40 ◽  
Author(s):  
Minzhao Huang ◽  
Su-Ni Tang ◽  
Ghanshyam Upadhyay ◽  
Justin L. Marsh ◽  
Christopher P. Jackman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Nude Mice ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells
Sign in / Sign up

Export Citation Format

Share Document