Mechanical stress signaling in pancreatic cancer cells triggers p38 MAPK- and JNK-dependent cytoskeleton remodeling and promotes cell migration via Rac1/Cdc42/Myosin II

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.

Download Full-text

Snail Recruits Ring1B to Mediate Transcriptional Repression and Cell Migration in Pancreatic Cancer Cells

Cancer Research ◽

10.1158/0008-5472.can-14-0181 ◽

2014 ◽

Vol 74 (16) ◽

pp. 4353-4363 ◽

Cited By ~ 46

Author(s):

Jiangzhi Chen ◽

Hong Xu ◽

Xiuqun Zou ◽

Jiamin Wang ◽

Yi Zhu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Transcriptional Repression ◽

Pancreatic Cancer Cells

Download Full-text

Brusatol inhibits growth and induces apoptosis in pancreatic cancer cells via JNK/p38 MAPK/NF-κb/Stat3/Bcl-2 signaling pathway

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2017.04.133 ◽

2017 ◽

Vol 487 (4) ◽

pp. 820-826 ◽

Cited By ~ 30

Author(s):

Yukai Xiang ◽

Wen Ye ◽

Chaohao Huang ◽

Bin Lou ◽

Jie Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

P38 Mapk ◽

Pancreatic Cancer Cells

Download Full-text

HOXA10 Promotes Cell Invasion and MMP-3 Expression Via TGFβ2-Mediated Activation of the p38 MAPK Pathway in Pancreatic Cancer Cells

Digestive Diseases and Sciences ◽

10.1007/s10620-014-3033-6 ◽

2014 ◽

Vol 59 (7) ◽

pp. 1442-1451 ◽

Cited By ~ 18

Author(s):

Xian-Ping Cui ◽

Cheng-Kun Qin ◽

Zhen-Hai Zhang ◽

Zhong-Xue Su ◽

Xin Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

P38 Mapk ◽

Cell Invasion ◽

Mapk Pathway ◽

Pancreatic Cancer Cells ◽

P38 Mapk Pathway

Download Full-text

Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrix metalloproteinase-9 and actin cytoskeleton remodeling

Laboratory Investigation ◽

10.1038/labinvest.2010.201 ◽

2011 ◽

Vol 91 (3) ◽

pp. 426-438 ◽

Cited By ~ 47

Author(s):

Kejun Zhang ◽

Dong Chen ◽

Xuelong Jiao ◽

Shaoyan Zhang ◽

Xiangping Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Matrix Metalloproteinase ◽

Actin Cytoskeleton ◽

Cancer Cells ◽

Matrix Metalloproteinase 9 ◽

Pancreatic Cancer Cells ◽

Cytoskeleton Remodeling ◽

Metalloproteinase 9

Download Full-text

TGF-β mediates PTEN suppression and cell motility through calcium-dependent PKC-α activation in pancreatic cancer cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00411.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. G899-G905 ◽

Cited By ~ 42

Author(s):

Jimmy Y. C. Chow ◽

Hui Dong ◽

Khai T. Quach ◽

Phuoc Nam Van Nguyen ◽

Kevin Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Migration ◽

Cancer Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Pten Expression ◽

Free Calcium ◽

Calcium Dependent ◽

Pancreatic Cancer Cells

Transforming growth factor-β (TGF-β) suppresses growth via the TGF-β-SMAD pathway but promotes growth in cancer cells with disrupted SMAD signaling and corresponds to an invasive phenotype. TGF-β also downregulates the tumor suppressor PTEN that is rarely mutated in sporadic pancreatic cancer; this downregulation may mediate cell proliferation and invasiveness, but the mechanism is unknown. Here, we examined whether TGF-β modulation of PTEN was mediated by protein kinase C (PKC). We have previously demonstrated that SMAD4-null BxPc-3 pancreatic cancer cells treated with TGF-β1 (10 ng/ml) suppressed PTEN expression and increased cell proliferation. TGF-β-treated cells were examined for PKC activation and its coupling to PTEN expression, utilizing pharmacological and knockdown methods. Calcium mobilization and cell migration were also examined. In BxPc-3 cells, only two PKC isoforms were activated by TGF-β, and PTEN downregulation by TGF-β was specifically mediated by PKC-α. In parallel, TGF-β rapidly induced an increase in cytoplasmic free calcium from intracellular stores, consistent with subsequent PKC-α activation. The TGF-β-induced increase in cell migration was blocked by knockdown of PKC-α. Thus calcium-dependent PKC-α mediates TGF-β-induced transcriptional downregulation of PTEN, and this pathway promotes cell migration in a SMAD4-null environment. The TGF-β-PKC-α-PTEN cascade may be a key pathway for pancreatic cancer cells to proliferate and metastasize.

Download Full-text

Periostin, secreted from stromal cells, has biphasic effect on cell migration and correlates with the epithelial to mesenchymal transition of human pancreatic cancer cells

International Journal of Cancer ◽

10.1002/ijc.23332 ◽

2008 ◽

Vol 122 (12) ◽

pp. 2707-2718 ◽

Cited By ~ 82

Author(s):

Atsushi Kanno ◽

Kennichi Satoh ◽

Atsushi Masamune ◽

Morihisa Hirota ◽

Kenji Kimura ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Stromal Cells ◽

Epithelial To Mesenchymal Transition ◽

Human Pancreatic Cancer ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

Biphasic Effect

Download Full-text

CCNI2 knockdown inhibits the proliferation, apoptosis and migration of pancreatic cancer cells

10.21203/rs.3.rs-24690/v2 ◽

2020 ◽

Author(s):

Bingyang Hu ◽

Wenzhi Zhang ◽

Changsheng Zhang ◽

Chonghui Li ◽

Ning Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Malignant Tumors ◽

Immunohistochemical Analysis ◽

Proliferation Capacity ◽

Pancreatic Cancer Cells ◽

And Migration ◽

Apoptosis Process ◽

Cyclin I

Abstract Background: Pancreatic cancer has been recognized as one of the most serious malignant tumors in the world, and its molecular mechanism is still not fully understood. Cyclin I-like (CCNI2) is a homolog of Cyclin I (CCNI), and at present its function is largely unknown. Methods: In this study, we aimed to explore the role of CCNI2 in the development of pancreatic cancer. The expression levels of CCNI2 in pancreatic cancer tissues and cells were detected by immunohistochemical analysis and qPCR, respectively. Lentivirus was used to deliver shRNA to pancreatic cancer cells to construct CCNI2 knockdown cell models. MTT and colony formation assays were used to assess cell proliferation capacity, flow cytometry was used to detect apoptosis, wound-healing and Transwell assays were used to determine cell migration. Results: Our results revealed that CCNI2 is not only highly expressed in pancreatic cancer, but also significantly correlated with pathological grade, pathological stage, and survival rate. It was confirmed that knockdown of CCNI2 inhibited the proliferation and cell migration of pancreatic cancer cells while promoting apoptosis. Furthermore, human apoptotic antibody arrays showed that CCNI2 is involved in apoptosis process by up-regulating the pro-apoptotic proteins. Conclusions: In conclusion, CCNI2 may be a prognostic marker for pancreatic cancer and is associated with its development. Thus, CCNI2 possesses potential to act as a therapeutic target for pancreatic cancer treatment.

Download Full-text