Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Jagadeeshan, S; Subramanian, A; Tentu, S; Beesetti, S; Singhal, M; Raghavan, S; Surabhi, RP; Mavuluri, J; Bhoopalan, H; Biswal, J; Pitani, RS; Chidambaram, S; Sundaram, S; Malathi, R; Jeyaraman, J; Nair, AS; Venkatraman, G; Rayala, SK.
P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer.
Ann Oncol. 2016; 27(8): 1546-1556.
Doi: 10.1093/annonc/mdw184
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- Führende Autor*innen der Med Uni Graz
- Muralikrishnan Anirudh Subramanian
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- Abstract:
- 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. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
- Find related publications in this database (using NLM MeSH Indexing)
- Adenocarcinoma - drug therapy
- Adenocarcinoma - genetics
- Adenocarcinoma - pathology
- Animals -
- Carcinoma, Pancreatic Ductal - drug therapy
- Carcinoma, Pancreatic Ductal - genetics
- Carcinoma, Pancreatic Ductal - pathology
- Cell Line, Tumor -
- DNA Damage - drug effects
- Deoxycytidine - administration & dosage
- Deoxycytidine - adverse effects
- Deoxycytidine - analogs & derivatives
- Drug Resistance, Neoplasm - genetics
- Epithelial-Mesenchymal Transition - drug effects
- Gene Expression Regulation, Neoplastic - drug effects
- Humans -
- Mice -
- Pancreatic Stellate Cells - drug effects
- Pancreatic Stellate Cells - pathology
- Xenograft Model Antitumor Assays -
- p21-Activated Kinases - genetics
- Find related publications in this database (Keywords)
- gemcitabine
- PAK1
- desmoplastic
- IPA-3
- resistance