title: 3'-Phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1) knockdown sensitizes non-small cell lung cancer cells to DNA damaging agents.
abstract: 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.
authors.affiliation: Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
authors.forename: Ada W Y
authors.initials: AW
authors.lastname: Leung
authors.affiliation: Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Wieslawa H
authors.initials: WH
authors.lastname: Dragowska
authors.affiliation: Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricaurte
authors.affiliation: Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Kwok
authors.affiliation: Terry Fox Laboratory, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Veena
authors.initials: V
authors.lastname: Mathew
authors.affiliation: Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.|Department of Pharmaceutical Sciences, Utrecht University, Utrecht, TB, 3508, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Roosendaal
authors.affiliation: Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Amith
authors.initials: A
authors.lastname: Ahluwalia
authors.affiliation: Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Corinna
authors.initials: C
authors.lastname: Warburton
authors.affiliation: Medical Oncology, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.|Department of Medicine, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
authors.forename: Janessa J
authors.initials: JJ
authors.lastname: Laskin
authors.affiliation: Terry Fox Laboratory, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6H 3N1, Canada.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Stirling
authors.affiliation: Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Qadir
authors.affiliation: Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada.|Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.|Centre for Drug Research and Development, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013430:Sulfate Adenylyltransferase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D009097:Multienzyme Complexes; D034741:RNA, Small Interfering; C022322:PAPS synthetase; D013430:Sulfate Adenylyltransferase; D002945:Cisplatin
keywords: DNA damage; PAPSS1; non-small cell lung cancer; sensitization; siRNA screen