TY - JOUR
T1 - Small molecule inhibitor against onco-mucins disrupts Src/FosL1 axis to enhance gemcitabine efficacy in pancreatic ductal adenocarcinoma
AU - Zhang, Chunmeng
AU - Atri, Pranita
AU - Nallasamy, Palanisamy
AU - Parte, Seema
AU - Rauth, Sanchita
AU - Nimmakayala, Rama Krishna
AU - Marimuthu, Saravanakumar
AU - Chirravuri-Venkata, Ramakanth
AU - Bhatia, Rakesh
AU - Halder, Sushanta
AU - Shah, Ashu
AU - Cox, Jesse L.
AU - Smith, Lynette
AU - Kumar, Sushil
AU - Foster, Jason M.
AU - Kukreja, Rakesh C.
AU - Seshacharyulu, Parthasarathy
AU - Ponnusamy, Moorthy P.
AU - Batra, Surinder K.
N1 - Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/12/28
Y1 - 2022/12/28
N2 - Mucin MUC4 is an aberrantly expressed oncogene in pancreatic ductal adenocarcinoma (PDAC), yet no pharmacological inhibitors have been identified to target MUC4. Here, we adapted an in silico screening method using the Cancer Therapeutic Response Database (CTRD) to Identify Small Molecule Inhibitors against Mucins (SMIMs). We identified Bosutinib as a candidate drug to target oncogenic mucins among 126 FDA-approved drugs from CTRD screening. Functionally, Bosutinib treatment alone/and in combination with gemcitabine (Gem)/5′ fluorouracil (5FU) reduced in vitro viability, migration, and colony formation in multiple PDAC cell lines as well as human PDAC organoid prolifertaion and growth and in vivo xenograft growth. Further, biochemical and molecular analyses showed that Bosutinib exhibited these functional effects by downregulating MUC4 mucin at both transcript and translation levels in a dose- and time-dependent manner. Mechanistically, global transcriptome analysis in PDAC cells upon treatment with Bosutinib revealed disruption of the Src-ERK/AKT-FosL1 pathway, leading to decreased expression of MUC4 and MUC5AC mucins. Taken together, Bosutinib is a promising, novel, and highly potent SMIMs to target MUC4/MUC5AC mucins. This mucin-targeting effect of Bosutinib can be exploited in the future with cytotoxic agents to treat mucinous tumors.
AB - Mucin MUC4 is an aberrantly expressed oncogene in pancreatic ductal adenocarcinoma (PDAC), yet no pharmacological inhibitors have been identified to target MUC4. Here, we adapted an in silico screening method using the Cancer Therapeutic Response Database (CTRD) to Identify Small Molecule Inhibitors against Mucins (SMIMs). We identified Bosutinib as a candidate drug to target oncogenic mucins among 126 FDA-approved drugs from CTRD screening. Functionally, Bosutinib treatment alone/and in combination with gemcitabine (Gem)/5′ fluorouracil (5FU) reduced in vitro viability, migration, and colony formation in multiple PDAC cell lines as well as human PDAC organoid prolifertaion and growth and in vivo xenograft growth. Further, biochemical and molecular analyses showed that Bosutinib exhibited these functional effects by downregulating MUC4 mucin at both transcript and translation levels in a dose- and time-dependent manner. Mechanistically, global transcriptome analysis in PDAC cells upon treatment with Bosutinib revealed disruption of the Src-ERK/AKT-FosL1 pathway, leading to decreased expression of MUC4 and MUC5AC mucins. Taken together, Bosutinib is a promising, novel, and highly potent SMIMs to target MUC4/MUC5AC mucins. This mucin-targeting effect of Bosutinib can be exploited in the future with cytotoxic agents to treat mucinous tumors.
KW - Bosutinib
KW - MUC4
KW - MUC5AC
KW - Pancreatic ductal adenocarcinoma
KW - SRC/ERK/FosL1
UR - http://www.scopus.com/inward/record.url?scp=85140063288&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85140063288&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2022.215922
DO - 10.1016/j.canlet.2022.215922
M3 - Article
C2 - 36285687
AN - SCOPUS:85140063288
SN - 0304-3835
VL - 551
JO - Cancer Letters
JF - Cancer Letters
M1 - 215922
ER -