3′-Phosphoadenosine 5′-phosphosulfate synthase 1 (PAPSS1) knockdown sensitizes non-small cell lung cancer cells to DNA damaging agents
Bibliographic record
Abstract
// Ada W. Y. Leung 1, 2 , Wieslawa H. Dragowska 1 , Daniel Ricaurte 1 , Brian Kwok 1 , Veena Mathew 3 , Jeroen Roosendaal 1, 4 , Amith Ahluwalia 1 , Corinna Warburton 1 , Janessa J. Laskin 5, 6 , Peter C. Stirling 3, 7 , Mohammed A. Qadir 1 , Marcel B. Bally 1, 2, 8, 9 1 Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada 2 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada 3 Terry Fox Laboratory, BC Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada 4 Department of Pharmaceutical Sciences, Utrecht University, Utrecht, TB, 3508, The Netherlands 5 Medical Oncology, BC Cancer Research Centre, Vancouver, BC, V5Z1L3, Canada 6 Department of Medicine, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada 7 Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada 8 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada 9 Centre for Drug Research and Development, Vancouver, BC, V6T 1Z3, Canada Correspondence to: Ada Leung e-mail: aleung@bccrc.ca Keywords: PAPSS1, sensitization, non-small cell lung cancer, siRNA screen, DNA damage Received: November 19, 2014 Accepted: March 23, 2015 Published: April 11, 2015 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 (IC 10 ) 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".