In Vivo Validation of PAPSS1 (3'-phosphoadenosine 5'-phosphosulfate synthase 1) as a Cisplatin-sensitizing Therapeutic Target.

Abstract

Purpose: Our previous screening efforts found that inhibition of PAPSS1 increases the potency of DNA-damaging agents in non-small cell lung cancer (NSCLC) cell lines. Here, we explored the clinical relevance of PAPSS1 and further investigated it as a therapeutic target in preclinical model systems.Experimental Design: PAPSS1 expression and cisplatin IC50 values were assessed in 52 lung adenocarcinoma cell lines. Effects of PAPSS1 inhibition on A549 cisplatin sensitivity under hypoxic and starvation conditions, in 3D spheroids, as well as in zebrafish and mouse xenografts, were evaluated. Finally, the association between PAPSS1 expression levels and survival in patients treated with standard chemotherapy was assessed.Results: Our results show a positive correlation between low PAPSS1 expression and increased cisplatin sensitivity in lung adenocarcinoma. In vitro, the potentiation effect was greatest when A549 cells were serum-starved under hypoxic conditions. When treated with low-dose cisplatin, PAPSS1-deficient A549 spheroids showed a 58% reduction in size compared with control cells. In vivo, PAPSS1 suppression and low-dose cisplatin treatment inhibited proliferation of lung tumor cells in zebrafish xenografts and significantly delayed development of subcutaneous tumors in mice. Clinical data suggest that NSCLC and ovarian cancer patients with low PAPSS1 expression survive longer following platinum-based chemotherapy.Conclusions: These results suggest that PAPSS1 inhibition enhances cisplatin activity in multiple preclinical model systems and that low PAPSS1 expression may serve as a biomarker for platin sensitivity in cancer patients. Developing strategies to target PAPSS1 activity in conjunction with platinum-based chemotherapy may offer an approach to improving treatment outcomes. Clin Cancer Res; 23(21); 6555-66. ©2017 AACR.

• Authors: Ada W Y Leung, Chansey J Veinotte, Nicole Melong, Min Hee Oh, Kent Chen, Katey S S Enfield, Ian Backstrom, Corinna Warburton, Donald Yapp, Jason N Berman, Marcel B Bally, William W Lockwood
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 21 Pg. 6555-6566 (Nov 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28790117 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Multienzyme Complexes
• PAPS synthetase
• Sulfate Adenylyltransferase
• Cisplatin

Topics

• A549 Cells
• Animals
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Proliferation (drug effects)
• Cisplatin (administration & dosage, adverse effects)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Multienzyme Complexes (genetics)
• Sulfate Adenylyltransferase (genetics)
• Xenograft Model Antitumor Assays