p21-Activated Kinase 4 (PAK4) as a Predictive Marker of Gemcitabine Sensitivity in Pancreatic Cancer Cell Lines
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Purpose p21-activated kinases (PAKs) are involved in cytoskeletal reorganization, gene transcription, cell proliferation and survival, and oncogenic transformation. Therefore, we hypothesized that PAK expression levels could predict the sensitivity of pancreatic cancer cells to gemcitabine treatment, and PAKs could be therapeutic targets. Materials and Methods Cell viability inhibition by gemcitabine was evaluated in human pancreatic cancer cell lines (Capan-1, Capan-2, MIA PaCa-2, PANC-1, Aspc-1, SNU-213, and SNU-410). Protein expression and mRNA of molecules was detected by immunoblot analysis and reverse transcription polymerase chain reaction. To define the function of PAK4, PAK4 was controlled using PAK4 siRNA. Results Capan-2, PANC-1, and SNU-410 cells were resistant to gemcitabine treatment. Immunoblot analysis of signaling molecules reported to indicate gemcitabine sensitivity showed higher expression of PAK4 and lower expression of human equilibrative nucleoside transporter 1 (hENT1), a well-known predictive marker for gemcitabine activity, in the resistant cell lines. Knockdown of PAK4 using siRNA induced the upregulation of hENT1. In resistant cell lines (Capan-2, PANC-1, and SNU-410), knockdown of PAK4 by siRNA resulted in restoration of sensitivity to gemcitabine. Conclusion PAK4 could be a predictive marker of gemcitabine sensitivity and a potential therapeutic target to increase gemcitabine sensitivity in pancreatic cancer.
Abstract
Purpose p21-activated kinases (PAKs) are involved in cytoskeletal reorganization, gene transcription, cell proliferation and survival, and oncogenic transformation. Therefore, we hypothesized that PAK expression levels could predict the sensitivity of pancreatic cancer cells to gemcitabine treatment, and PAKs could be therapeutic targets. Materials and Methods Cell viability inhibition by gemcitabine was evaluated in human pancreatic cancer cell lines (Capan-1, Capan-2, MIA PaCa-2, PANC-1, Aspc-1, SNU-213, and SNU-410). Protein expression and mRNA of molecules was detected by immunoblot analysis and reverse transcription polymerase chain reaction. To define the function of PAK4, PAK4 was controlled using PAK4 siRNA. Results Capan-2, PANC-1, and SNU-410 cells were resistant to gemcitabine treatment. Immunoblot analysis of signaling molecules reported to indicate gemcitabine sensitivity showed higher expression of PAK4 and lower expression of human equilibrative nucleoside transporter 1 (hENT1), a well-known predictive marker for gemcitabine activity, in the resistant cell lines. Knockdown of PAK4 using siRNA induced the upregulation of hENT1. In resistant cell lines (Capan-2, PANC-1, and SNU-410), knockdown of PAK4 by siRNA resulted in restoration of sensitivity to gemcitabine. Conclusion PAK4 could be a predictive marker of gemcitabine sensitivity and a potential therapeutic target to increase gemcitabine sensitivity in pancreatic cancer.
참고문헌 (24)
- Von Hoff DD, "Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine", N Engl J Med, 369, pp.1691~1703 (2013)
- Moore MJ, "Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer : a phase III trial of the National Cancer Institute of Canada Clinical Trials Group", J Clin Oncol, 25, pp.1960~1966 (2007)
- Colucci G, "Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as firstline treatment of patients with advanced pancreatic cancer : the GIP-1 study", J Clin Oncol, 28, pp.1645~1651 (2010)
- Cunningham D, "Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer", J Clin Oncol, 27, pp.5513~5518 (2009)
- Poplin E, "Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine(fixed-dose rate infusion)compared with gemcitabine(30-minute infusion)in patients with pancreatic carcinoma E6201 : a trial of the Eastern Cooperative Oncology Group", J Clin Oncol, 27, pp.3778~3785 (2009)
- Oettle H, "Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer : a randomized controlled trial", JAMA, 297, pp.267~277 (2007)
- Molli PR, "PAK signaling in oncogenesis", Oncogene, 28, pp.2545~2555 (2009)
- Arias-Romero LE, "A tale of two Paks", Biol Cell, 100, pp.97~108 (2008)
- Dummler B, "Pak protein kinases and their role in cancer", Cancer Metastasis Rev, 28, pp.51~63 (2009)
- Kumar R, "p21-activated kinases in cancer", Nat Rev Cancer, 6, pp.459~471 (2006)
- Crawford JJ, "p21-Activated kinase inhibitors : a patent review", Expert Opin Ther Pat, 22, pp.293~310 (2012)
- He H, "p21-activated kinases and gastrointestinal cancer", Biochim Biophys Acta, 1833, pp.33~39 (2013)
- Ong CC, "Targeting p21-activated kinase 1(PAK1)to induce apoptosis of tumor cells", Proc Natl Acad Sci U S A, 108, pp.7177~7182 (2011)
- Chen S, "Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification", Cancer Biol Ther, 7, pp.1793~1802 (2008)
- Lee SH, "Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway", Cell Death Dis, 2, pp.e235~ (2011)
- Chauhan SC, "MUC13 mucin augments pancreatic tumorigenesis", Mol Cancer Ther, 11, pp.24~33 (2012)
- Deer EL, "Phenotype and genotype of pancreatic cancer cell lines", Pancreas, 39, pp.425~435 (2010)
- Ja Lok Ku, "Biology of SNU Cell Lines", Cancer Research and Treatment, 37(1), pp.1~19 (2005), 대한암학회
- Qu J, "Activated PAK4 regulates cell adhesion and anchorageindependent growth", Mol Cell Biol, 21, pp.3523~3533 (2001)
- Li X, "PAK4 functions in tumor necrosis factor(TNF)alpha-induced survival pathways by facilitating TRADD binding to the TNF receptor", J Biol Chem, 280, pp.41192~41200 (2005)
- Siu MK, "p21-Activated kinase-1 promotes aggressive phenotype, cell proliferation, and invasion in gestational trophoblastic disease", Am J Pathol, 176, pp.3015~3022 (2010)
- Ahn HK, "P21-activated kinase 4 overexpression in metastatic gastric cancer patients", Transl Oncol, 4, pp.345~349 (2011)
- Marechal R, "Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma", Gastroenterology, 143, pp.664~674 (2012)
- Greenhalf W, "Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial", J Natl Cancer Inst, 106, pp.347~ (2014)