Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/22634
Title: Antitumor effects of all-trans retinoic acid and its synergism with gemcitabine are associated with downregulation of p21-activated kinases in pancreatic cancer.
Authors: Wang, Kai;Baldwin, Graham S;Nikfarjam, Mehrdad;He, Hong
Affiliation: Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: 1-May-2019
EDate: 2019-05-01
Citation: American journal of physiology. Gastrointestinal and liver physiology 2019; 316(5): G632-G640
Abstract: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies worldwide. All-trans retinoic acid (ATRA) has been used as an antistromal agent in PDA, and its antitumor effect has also been reported in various kinds of cancer, including PDA. Inhibition of p21-activated kinases (PAKs) is associated with decreased tumor growth and increased gemcitabine sensitivity. The aim of this study was to evaluate the inhibitory effects of ATRA alone and in combination with gemcitabine on cell growth and migration of wild-type and gemcitabine-resistant PDA cells and the potential mechanism(s) involved. Human (MiaPaCa-2) and murine (TB33117) PDA cell lines were incubated in increasing concentrations of gemcitabine to establish resistant clones. Cell growth, clonogenicity, and migration/invasion were determined using a sulforhodamine B assay, a colony formation assay, and a Boyden chamber assay, respectively. Protein expression was measured by Western blotting. ATRA reduced cell proliferation, colony formation, and migration/invasion in both wild-type and gemcitabine-resistant cell lines. PAK1 expression was significantly increased in resistant cells. Cells treated with ATRA showed decreased expression of PAK1, PAK2, PAK4, and α-smooth muscle actin. The combination of ATRA and gemcitabine synergistically reduced cell growth in both wild-type and gemcitabine-resistant cell lines. Depletion of PAK1 enhanced ATRA sensitivity in MiaPaCa-2 cells. In conclusion, the antitumor effects of ATRA and its synergism with gemcitabine are associated with downregulation of PAKs. NEW & NOTEWORTHY The inhibitory effect of all-trans retinoic acid (ATRA) on cell proliferation, colony formation, and migration/invasion was associated with downregulation of p21-activated kinases (PAKs), and depletion of PAK1 enhanced ATRA sensitivity in MiaPaCa-2 cells. The combination of ATRA and gemcitabine synergistically reduced cell growth in both wild-type and gemcitabine-resistant pancreatic ductal adenocarcinoma cells. As an important prognostic marker, α-smooth muscle actin also can be downregulated by ATRA in pancreatic ductal adenocarcinoma cells.
URI: http://ahro.austin.org.au/austinjspui/handle/1/22634
DOI: 10.1152/ajpgi.00344.2018
ORCID: 0000-0003-4152-8752
0000-0002-0944-8747
0000-0003-4866-276X
0000-0002-2342-8750
PubMed URL: 30844294
Type: Journal Article
Research Support, Non-U.S. Gov't
Subjects: all-trans retinoic acid
chemo-resistance
gemcitabine
p21-activated kinases
pancreatic ductal adenocarcinoma
Appears in Collections:Journal articles

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