YM155 induces EGFR suppression in pancreatic cancer cells.

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.

• Authors: Young-Soon Na, Soo-Jin Yang, Seung-Mi Kim, Kyung-Ah Jung, Jai-Hee Moon, Jae-Sik Shin, Dok Hyun Yoon, Yong Sang Hong, Min-Hee Ryu, Jae-Lyun Lee, Jung Shin Lee, Tae Won Kim
• Journal: PloS one (PLoS One) Vol. 7 Issue 6 Pg. e38625 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22723871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Imidazoles
• Inhibitor of Apoptosis Proteins
• Naphthoquinones
• STAT3 Transcription Factor
• Survivin
• X-Linked Inhibitor of Apoptosis Protein
• ErbB Receptors
• Extracellular Signal-Regulated MAP Kinases
• sepantronium

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Line, Tumor
• ErbB Receptors (genetics, metabolism)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Imidazoles (administration & dosage, pharmacology)
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Inhibitory Concentration 50
• Mice
• Mice, Nude
• Naphthoquinones (administration & dosage, pharmacology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphorylation (drug effects)
• Promoter Regions, Genetic
• Proteolysis
• STAT3 Transcription Factor (genetics, metabolism)
• Survivin
• Tumor Burden (drug effects)
• Ubiquitination (drug effects)
• X-Linked Inhibitor of Apoptosis Protein (metabolism)
• Xenograft Model Antitumor Assays