YM155 induces EGFR suppression in pancreatic cancer cells.
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.
Institute for Innovate Cancer Research, Asan Medical Center, Seoul, Korea.
Young-Soon
YS
Na
Soo-Jin
SJ
Yang
Seung-Mi
SM
Kim
Kyung-Ah
KA
Jung
Jai-Hee
JH
Moon
Jae-Sik
JS
Shin
Dok Hyun
DH
Yoon
Yong Sang
YS
Hong
Min-Hee
MH
Ryu
Jae-Lyun
JL
Lee
Jung Shin
JS
Lee
Tae Won
TW
Kim
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D009285:Naphthoquinones / Q000008:administration & dosage / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D047368:Tumor Burden / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D019869:Phosphatidylinositol 3-Kinases; D050796:STAT3 Transcription Factor; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C107489:BIRC5 protein, human; C523798:sepantronium