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Therapeutic Gene Delivery and Transfection in Human Pancreatic Cancer Cells using Epidermal Growth Factor Receptor-targeted Gelatin Nanoparticles
Published on: January 4, 2012
YM155 induces EGFR suppression in pancreatic cancer cells
Young-Soon Na1, Soo-Jin Yang, Seung-Mi Kim
1Institute for Innovate Cancer Research, Asan Medical Center, Seoul, Korea.
Abstract:
YM155, which inhibits the anti-apoptotic protein survivin, is known to exert anti-tumor effects in various cancers, including prostate and lung cancer. However, there are few reports describing the inhibitory effect of YM155 on human pancreatic cancers that highly express survivin. Here, we tested the effects of YM155 on a variety of cancer cell lines, including pancreatic cancer cells. We found that YM155 exerts an anti-proliferative effect in pancreatic cancer cells, inducing cell death through suppression of XIAP (X-linked inhibitor of apoptosis) as well as survivin without affecting the anti-apoptotic proteins Bcl-xL or Mcl-1. YM155 also inhibited tumor growth in vivo, reducing the size of pancreatic cancer cell line MIAPaCa-2 xenografts by 77.1% on day 31. Western blot analyses further showed that YM155 downregulated phosphoinoside 3-kinase (PI3K) expression and reduced the levels of phosphorylated (activated) extracellular signal-regulated kinase (ERK) and STAT3 (signal transducer and activator of transcription 3) in PANC-1 cells. Interestingly, we also found that YM155 downregulated the epidermal growth factor receptor (EGFR) in various cancer cell lines and induced the EGFR phosphorylation and ubiquitination of EGFR in PANC-1 cells. YM155 also modestly promoted the ubiquitination of survivin and XIAP. Therefore, YM155 acts through modulation of EGFR and survivin expression to subsequently reduce survival. We suggest that YM155 has potential as a therapeutic agent in the treatment of pancreatic cancer.
Insights
The survivin inhibitor YM155 shows anti-cancer effects in pancreatic cancer cells. It reduces tumor growth by targeting survivin and X-linked inhibitor of apoptosis (XIAP), suggesting potential as a pancreatic cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Survivin is an anti-apoptotic protein highly expressed in many cancers, including pancreatic cancer.
- YM155 is a survivin inhibitor with known anti-tumor effects in prostate and lung cancers.
- Limited data exists on YM155's efficacy in human pancreatic cancers expressing survivin.
Purpose of the Study:
- To investigate the anti-proliferative and cell death-inducing effects of YM155 on human pancreatic cancer cells.
- To elucidate the molecular mechanisms underlying YM155's action in pancreatic cancer.
- To evaluate the in vivo efficacy of YM155 in a pancreatic cancer xenograft model.
Main Methods:
- In vitro cell proliferation and cell death assays using various cancer cell lines, including pancreatic cancer cells.
- Western blot analysis to assess protein expression levels (survivin, XIAP, Bcl-xL, Mcl-1, PI3K, p-ERK, STAT3, EGFR).
- In vivo studies using MIAPaCa-2 pancreatic cancer xenografts in mice to evaluate tumor growth inhibition.
Main Results:
- YM155 demonstrated significant anti-proliferative effects and induced cell death in pancreatic cancer cells by suppressing survivin and X-linked inhibitor of apoptosis (XIAP).
- YM155 inhibited tumor growth in vivo, reducing xenograft size by 77.1%.
- YM155 downregulated phosphoinositide 3-kinase (PI3K), reduced phosphorylated extracellular signal-regulated kinase (ERK) and STAT3, downregulated epidermal growth factor receptor (EGFR), and promoted ubiquitination of EGFR, survivin, and XIAP.
Conclusions:
- YM155 effectively inhibits pancreatic cancer cell proliferation and tumor growth, acting through the modulation of EGFR and survivin pathways.
- YM155 induces cell death by suppressing survivin and XIAP, without affecting Bcl-xL or Mcl-1.
- YM155 shows promise as a potential therapeutic agent for pancreatic cancer treatment.
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