P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer.
Therapeutic resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) is attributed to various cellular mechanisms and signaling molecules that influence as a single factor or in combination.



In this study, utilizing in vitro p21-activated kinase 1 (Pak1) overexpression and knockdown cell line models along with in vivo athymic mouse tumor xenograft models and clinical samples, we demonstrate that Pak1 is a crucial signaling kinase in gemcitabine resistance.



Pak1 kindles resistance via modulation of epithelial-mesenchymal transition and activation of pancreatic stellate cells. Our results from gemcitabine-resistant and -sensitive cell line models showed that elevated Pak1 kinase activity is required to confer gemcitabine resistance. This was substantiated by elevated levels of phosphorylated Pak1 and ribonucleotide reductase M1 levels in the majority of human PDAC tumors when compared with normal. Delineation of the signaling pathway revealed that Pak1 confers resistance to gemcitabine by preventing DNA damage, inhibiting apoptosis and regulating survival signals via NF-κB. Furthermore, we found that Pak1 is an upstream interacting substrate of transforming growth factor β-activated kinase 1-a molecule implicated in gemcitabine resistance. Molecular mechanistic studies revealed that gemcitabine docks with the active site of Pak1; furthermore, gemcitabine treatment induces Pak1 kinase activity both in vivo and in cell-free system. Finally, results from athymic mouse tumor models illustrated that Pak1 inhibition by IPA-3 enhances the cytotoxicity of gemcitabine and brings about pancreatic tumor regression.



To our knowledge, this is the first study illustrating the mechanistic role of Pak1 in causing gemcitabine resistance via multiple signaling crosstalks, and hence Pak1-specific inhibitors will prove to be a better adjuvant with existing chemotherapy modality for PDAC.
Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai Department of Genetics, University of Madras, Chennai.
S
S
Jagadeeshan
Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai.
A
A
Subramanian
Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai.
S
S
Tentu
Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai.
S
S
Beesetti
Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai.
M
M
Singhal
Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai.
S
S
Raghavan
Department of Human Genetics.
R P
RP
Surabhi
Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai.
J
J
Mavuluri
Department of Human Genetics.
H
H
Bhoopalan
Department of Bioinformatics, Alagappa University, Karaikudi.
J
J
Biswal
Department of CEFT.
R S
RS
Pitani
Department of CEFT.
S
S
Chidambaram
Department of Pathology, Sri Ramachandra University, Porur, Chennai.
S
S
Sundaram
Department of Genetics, University of Madras, Chennai.
R
R
Malathi
Department of Bioinformatics, Alagappa University, Karaikudi.
J
J
Jeyaraman
Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, Kerala, India.
A S
AS
Nair
Department of Human Genetics.
G
G
Venkatraman
Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai rayala@iitm.ac.in.
S K
SK
Rayala
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D058954:Pancreatic Stellate Cells / Q000187:drug effects / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000235:genetics*; D000093542:Gemcitabine
D003841:Deoxycytidine; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D000093542:Gemcitabine
IPA-3; PAK1; desmoplastic; gemcitabine; resistance