Abstract
BackgroundPancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care. Although growing evidence shows that p21-activated kinase 1 (PAK1) plays a crucial role in pancreatic cancer, its role has not been fully elucidated. This study aimed to characterise the expression and functional relevance of PAK1 in pancreatic cancer.MethodsPAK1 expression was measured in pancreatic cancer specimens by immunohistochemistry and in pancreatic cancer cell lines by western blotting. The effect of inhibition of PAK1 by either shRNA knock-down (KD), or by a selective inhibitor, FRAX597, alone or in combination with gemcitabine, on cell proliferation and migration/invasion was measured by thymidine uptake and Boyden chamber assays, respectively. The effect on tumour growth and survival was assessed in orthotopic murine models.ResultsPAK1 was expressed in all human pancreatic cancer samples tested, an7d was upregulated in all pancreatic cancer cell lines tested. PAK1 KD inhibited pancreatic cancer cell growth and survival, and increased sensitivity to gemcitabine treatment. AKT activity and HIF1α expression were also inhibited. FRAX597 inhibited pancreatic cancer cell proliferation, survival, and migration/invasion. When combined with gemcitabine, FRAX597 synergistically inhibited pancreatic cancer proliferation in vitro and inhibited tumour growth in vivo.ConclusionsThese results implicate PAK1 as a regulator of pancreatic cancer cell growth and survival. Combination of a PAK1 inhibitor such as FRAX597 with cytotoxic chemotherapy deserves further study as a novel therapeutic approach to pancreatic cancer treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2057-z) contains supplementary material, which is available to authorized users.
Highlights
Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours
We have previously found that a non-selective p21-activated kinases (PAKs) inhibitor, glaucarubinone, reduced pancreatic cancer growth, and that treatment in combination with gemcitabine resulted in synergistic inhibition [10]
p21-activated kinase 1 (PAK1) is expressed in human pancreatic cancer and upregulated in pancreatic cancer cell lines PAK1 staining of pancreatic ductal adenocarcinoma cells was observed in all 10 human pancreatic cancer samples tested (Fig. 1a)
Summary
Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care. Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours. It is the fourth leading cause of cancer-related mortality in Australia and the United States and is expected to become the second leading cause of cancer-related deaths by 2030, based on current management with no significant treatment improvements [1]. Combinational chemotherapies exist such as FOLFIRINOX and gemcitabine with nab-paclitaxel, as a single agent, gemcitabine remains the standard of care for the treatment of pancreatic cancer in most countries [3]. The limited treatment regimens and predicted increase in cancer-related mortality highlight the urgent need for the development of effective therapies based on our understanding of the molecular mechanisms involved in pancreatic cancer
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