Abstract
Transmembrane proteins MUC4, EGFR and HER2 are shown to be critical in invasion and metastasis of pancreatic cancer. Besides, we and others have demonstrated de novo expression of MUC4 in ~70-90% of pancreatic cancer patients and its stabilizing effects on HER2 downstream signaling in pancreatic cancer. Here, we found that use of canertinib or afatinib resulted in reduction of MUC4 and abrogation of in vitro and in vivo oncogenic functions of MUC4 in pancreatic cancer cells. Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1. Furthermore, canertinib and afatinib treatment also inhibited proliferation, migration and survival of pancreatic cancer cells by attenuation of signaling events including pERK1/2 (T202/Y204), cyclin D1, cyclin A, pFAK (Y925) and pAKT (Ser473). Using in vivo bioluminescent imaging, we demonstrated that canertinib treatment significantly reduced tumor burden (P=0.0164) and metastasis to various organs. Further, reduced expression of MUC4 and EGFR family members were confirmed in xenografts. Our results for the first time demonstrated the targeting of EGFR family members along with MUC4 by using pan-EGFR inhibitors. In conclusion, our studies will enhance the translational acquaintance of pan-EGFR inhibitors for combinational therapies to combat against lethal pancreatic cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5164-5181 |
| Number of pages | 18 |
| Journal | Oncotarget |
| Volume | 6 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jan 1 2015 |
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Keywords
- Afatinib
- Canertinib
- EGFR
- MUC4
- Pancreatic cancer
ASJC Scopus subject areas
- Oncology
Cite this
Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer. / Seshacharyulu, Parthasarathy; Palanimuthu Ponnusamy, Moorthy; Rachagani, Satyanarayana; Lakshmanan, Imayavaramban; Haridas, Dhanya; Yan, Ying; Ganti, Apar Kishor P; Batra, Surinder Kumar.
In: Oncotarget, Vol. 6, No. 7, 01.01.2015, p. 5164-5181.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer
AU - Seshacharyulu, Parthasarathy
AU - Palanimuthu Ponnusamy, Moorthy
AU - Rachagani, Satyanarayana
AU - Lakshmanan, Imayavaramban
AU - Haridas, Dhanya
AU - Yan, Ying
AU - Ganti, Apar Kishor P
AU - Batra, Surinder Kumar
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Transmembrane proteins MUC4, EGFR and HER2 are shown to be critical in invasion and metastasis of pancreatic cancer. Besides, we and others have demonstrated de novo expression of MUC4 in ~70-90% of pancreatic cancer patients and its stabilizing effects on HER2 downstream signaling in pancreatic cancer. Here, we found that use of canertinib or afatinib resulted in reduction of MUC4 and abrogation of in vitro and in vivo oncogenic functions of MUC4 in pancreatic cancer cells. Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1. Furthermore, canertinib and afatinib treatment also inhibited proliferation, migration and survival of pancreatic cancer cells by attenuation of signaling events including pERK1/2 (T202/Y204), cyclin D1, cyclin A, pFAK (Y925) and pAKT (Ser473). Using in vivo bioluminescent imaging, we demonstrated that canertinib treatment significantly reduced tumor burden (P=0.0164) and metastasis to various organs. Further, reduced expression of MUC4 and EGFR family members were confirmed in xenografts. Our results for the first time demonstrated the targeting of EGFR family members along with MUC4 by using pan-EGFR inhibitors. In conclusion, our studies will enhance the translational acquaintance of pan-EGFR inhibitors for combinational therapies to combat against lethal pancreatic cancer.
AB - Transmembrane proteins MUC4, EGFR and HER2 are shown to be critical in invasion and metastasis of pancreatic cancer. Besides, we and others have demonstrated de novo expression of MUC4 in ~70-90% of pancreatic cancer patients and its stabilizing effects on HER2 downstream signaling in pancreatic cancer. Here, we found that use of canertinib or afatinib resulted in reduction of MUC4 and abrogation of in vitro and in vivo oncogenic functions of MUC4 in pancreatic cancer cells. Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1. Furthermore, canertinib and afatinib treatment also inhibited proliferation, migration and survival of pancreatic cancer cells by attenuation of signaling events including pERK1/2 (T202/Y204), cyclin D1, cyclin A, pFAK (Y925) and pAKT (Ser473). Using in vivo bioluminescent imaging, we demonstrated that canertinib treatment significantly reduced tumor burden (P=0.0164) and metastasis to various organs. Further, reduced expression of MUC4 and EGFR family members were confirmed in xenografts. Our results for the first time demonstrated the targeting of EGFR family members along with MUC4 by using pan-EGFR inhibitors. In conclusion, our studies will enhance the translational acquaintance of pan-EGFR inhibitors for combinational therapies to combat against lethal pancreatic cancer.
KW - Afatinib
KW - Canertinib
KW - EGFR
KW - MUC4
KW - Pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=84925002884&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84925002884&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3286
DO - 10.18632/oncotarget.3286
M3 - Article
C2 - 25686822
AN - SCOPUS:84925002884
VL - 6
SP - 5164
EP - 5181
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 7
ER -