Simultaneous Knock-down of Bcl-xL and Mcl-1 Induces Apoptosis in Gemcitabine-Sensitive and -Resistant Pancreatic Cancer Cells

2012 ◽  
Vol 172 (2) ◽  
pp. 222-223
Author(s):  
H. Takahashi ◽  
E.Y. Brovman ◽  
Y. Matsuo ◽  
H. Ishiguro ◽  
M. Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Knock Down ◽  
Pancreatic Cancer Cells

Silencing of Astrocyte elevated gene-1 (AEG-1) inhibits proliferation, migration, and invasiveness, and promotes apoptosis in pancreatic cancer cells

2019 ◽  
Vol 97 (2) ◽  
pp. 165-175 ◽  
Author(s):  
Xing Yang ◽  
Shaowei Song
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Hairpin Rna ◽  
Knock Down ◽  
Pancreatic Cancers ◽  
Pancreatic Cancer Cells ◽  
Apoptosis Assay ◽  
Matrix Metallopeptidase ◽  
Coated Membrane

To investigate the role of Astrocyte elevated gene-1 (AEG-1) in the development and progress of pancreatic cancer, short hairpin RNA (shRNA) was inserted into the RNA interference vector to knock-down the endogenous AEG-1 in two pancreatic cancer cell lines: AsPC-1 and PANC-1. Our results showed that silencing of AEG-1 suppressed the proliferation, colony formation ability, and cell stemness of AsPC-1 and PANC-1 cells, and inhibited their G1-to-S phase transition. Results from apoptosis assay showed that knock-down of AEG-1 led to cell apoptosis. The expression of anti-apoptotic Bcl-2 was downregulated and that of the pro-apoptotic Bax and cleaved caspase-3 was upregulated in AEG-1-silenced pancreatic cancer cells. Further, the capability of AEG-1-silenced cells to migrate and to invade through the Matrigel-coated membrane was weaker, and the expression of matrix metallopeptidase 2 (MMP-2) and MMP-9 were decreased. Moreover, the AKT–β-catenin signaling pathway was inhibited in the cells with knock-down of AEG-1. In addition, the growth of xenograft tumors formed by AsPC-1 and PANC-1 cells was suppressed by AEG-1 shRNA. In conclusion, our study demonstrates that pancreatic cancer cells require AEG-1 to maintain their survival and metastasis, suggesting AEG-1 as a potential target for the treatment of pancreatic cancers.

Effect of inhibition of protein kinase C delta (PKCδ) on pancreatic cancer cells.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14591-e14591 ◽  
Author(s):  
George P. Sorescu ◽  
Lora W. Forman ◽  
Douglas V. Faller
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Caspase Inhibitor ◽  
Knock Down ◽  
Pancreatic Cancers ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Cancer Stem Cells

e14591 Background: 93% of pancreatic cancers have activating mutations in the K-Ras gene. We have previously shown that mutated, constitutively-activated Ras is lethal to cells if an essential Ras-driven survival pathway is disrupted by suppression of PKCδ. PKCδ has various cellular functions, but is not required for the survival of normal cells and its inhibition in vitro or in vivo has no known adverse effects. Signal transducer and activator of transcription 3 (STAT3) is constitutive driver of many solid cancers, including pancreatic cancers. STAT3 requires phosphorylation of Tyr 705 for activation and, once activated translocates to the nucleus, where it controls genes involved in cell survival or death. Methods: Human pancreatic cancer cell lines PancI, MIAPACA and primary human pancreatic cancer stem cells were studied. shRNA-mediated knockdown of PKCδ, with scrambled shRNA as a control, was used to validate PKCδ as a target. Rottlerin and KAM1 were used as relatively specific PKCδ inhibitors. For inhibition of STAT3, specific shRNA against STAT3 versus scrambled shRNA were employed for knock-downs. For cytotoxicity analyses, MTS assays were used to assess cell growth. Z-vad-FMK was used as a pan-caspase inhibitor. Immunoblotting was used to verify knock-down of PKCδ or STAT3 and to quantify the phosphorylation status of STAT3 phospho-Tyr 705. Results: PKCδ inhibition by either shRNA knock-down or inhibitor led to dephosphorylation of STAT3 at Tyr 705, extensive cytotoxicity of pancreatic cancer cells and dramatic reductions in tumor clonogenic capacity. Knock down of STAT3 was equally cytotoxic to pancreatic cancer cells. Cytotoxicity following PKCδ inhibition was not prevented by a pan-caspase inhibitor. Conclusions: Activated STAT3 and survival in pancreatic cancer cells requires PKCδ. Inhibition of PKCδ, and subsequent suppression of STAT3 activation, is cytotoxic for pancreatic cancer cells through a mechanism independent of caspase activation or apoptosis. Small molecule inhibitors of PKCδ have potential as targeted therapeutic agents against pancreatic tumors, pancreatic cancer stem cells, and other human tumors with mutational activation of Ras.

scholarly journals Simultaneous knock-down of Bcl-xL and Mcl-1 induces apoptosis through Bax activation in pancreatic cancer cells

2013 ◽  
Vol 1833 (12) ◽  
pp. 2980-2987 ◽  
Author(s):  
Hiroki Takahashi ◽  
Monica C. Chen ◽  
Hung Pham ◽  
Yoichi Matsuo ◽  
Hideyuki Ishiguro ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Knock Down ◽  
Pancreatic Cancer Cells
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