3’-Phosphoadenosine 5’-phosphosulfate synthase 1 (PAPSS1) knockdown sensitizes non-small cell lung cancer cells to DNA damaging agents
Metrics: PDF 1576 views | HTML 1852 views | ?
Ada W. Y. Leung1,2, Wieslawa H. Dragowska1, Daniel Ricaurte1, Brian Kwok1, Veena Mathew3, Jeroen Roosendaal1,4, Amith Ahluwalia1, Corinna Warburton1, Janessa J. Laskin5,6, Peter C. Stirling3,7, Mohammed A. Qadir1, Marcel B. Bally1,2,8,9
1Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada
2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada
3Terry Fox Laboratory, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada
4Department of Pharmaceutical Sciences, Utrecht University, Utrecht, TB, 3508, The Netherlands
5Medical Oncology, BC Cancer Research Centre, Vancouver, BC, V5Z1L3, Canada
6Department of Medicine, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada
7Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
8Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
9Centre for Drug Research and Development, Vancouver, BC, V6T 1Z3, Canada
Ada Leung e-mail: email@example.com
Keywords: PAPSS1, sensitization, non-small cell lung cancer, siRNA screen, DNA damage
Received: November 19, 2014 Accepted: March 23, 2015 Published: April 11, 2015
Standard treatment for advanced non-small cell lung cancer (NSCLC) with no known driver mutation is platinum-based chemotherapy, which has a response rate of only 30–33%. Through an siRNA screen, 3′-phosphoadenosine 5′-phosphosulfate (PAPS) synthase 1 (PAPSS1), an enzyme that synthesizes the biologically active form of sulfate PAPS, was identified as a novel platinum-sensitizing target in NSCLC cells. PAPSS1 knockdown in combination with low-dose (IC10) cisplatin reduces clonogenicity of NSCLC cells by 98.7% (p < 0.001), increases DNA damage, and induces G1/S phase cell cycle arrest and apoptosis. PAPSS1 silencing also sensitized NSCLC cells to other DNA crosslinking agents, radiation, and topoisomerase I inhibitors, but not topoisomerase II inhibitors. Chemo-sensitization was not observed in normal epithelial cells. Knocking out the PAPSS1 homolog did not sensitize yeast to cisplatin, suggesting that sulfate bioavailability for amino acid synthesis is not the cause of sensitization to DNA damaging agents. Rather, sensitization may be due to sulfation reactions involved in blocking the action of DNA damaging agents, facilitating DNA repair, promoting cancer cell survival under therapeutic stress or reducing the bioavailability of DNA damaging agents. Our study demonstrates for the first time that PAPSS1 could be targeted to improve the activity of multiple anticancer agents used to treat NSCLC.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.