Perla Pucci1,2, Erik Venalainen3, Ilaria Alborelli4, Luca Quagliata5, Cheryl Hawkes1, Rebecca Mather1, Ignacio Romero1, Sushilaben H Rigas1, Yuzhuo Wang3,6,7, Francesco Crea1,3. 1. School of Life, Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, Buckinghamshire, MK7 6AA, UK. 2. Present address: Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, CB20QQ, UK. 3. Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada. 4. Institute of Pathology, University Hospital Basel, Basel 4031, Switzerland. 5. Global Head of Medical Affairs, Clinical NGS & Oncology Division, Life Sciences Solutions, Thermo Fisher Scientific, Baarerstrasse, Switzerland. 6. The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC V6H 3Z6, Canada. 7. Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
Abstract
Background: Castration-resistant prostate cancer (CRPC) is an incurable malignancy. Long noncoding RNAs (lncRNAs) play key roles in drug resistance. Materials & methods: LncRNA HORAS5 role in cabazitaxel resistance (i.e., cell-count, IC50 and caspase activity) was studied via lentiviral-mediated overexpression and siRNA-based knockdown. Genes expression was analyzed with RNA-sequencing, reverse transcription quantitative PCR (RT-qPCR) and western blot. HORAS5 expression was queried in clinical database. Results: Cabazitaxel increased HORAS5 expression that upregulated BCL2A1, thereby protecting CRPC cells from cabazitaxel-induced apoptosis. BCL2A1 knockdown decreased cell-count and increased apoptosis in CRPC cells. HORAS5-targeting antisense oligonucleotide decreased cabazitaxel IC50. In CRPC clinical samples, HORAS5 expression increased upon taxane treatment. Conclusion: HORAS5 stimulates the expression of BCL2A1 thereby decreasing apoptosis and enhancing cabazitaxel resistance in CRPC cells.
Background: Castration-resistant prostate cancer (CRPC) is an incurable malignancy. Long noncoding RNAs (lncRNAs) play key roles in drug resistance. Materials & methods: LncRNA HORAS5 role in cabazitaxel resistance (i.e., cell-count, IC50 and caspase activity) was studied via lentiviral-mediated overexpression and siRNA-based knockdown. Genes expression was analyzed with RNA-sequencing, reverse transcription quantitative PCR (RT-qPCR) and western blot. HORAS5 expression was queried in clinical database. Results:Cabazitaxel increased HORAS5 expression that upregulated BCL2A1, thereby protecting CRPC cells from cabazitaxel-induced apoptosis. BCL2A1 knockdown decreased cell-count and increased apoptosis in CRPC cells. HORAS5-targeting antisense oligonucleotide decreased cabazitaxel IC50. In CRPC clinical samples, HORAS5 expression increased upon taxane treatment. Conclusion: HORAS5 stimulates the expression of BCL2A1 thereby decreasing apoptosis and enhancing cabazitaxel resistance in CRPC cells.
Entities:
Keywords:
BCL2A1; HORAS5; castration-resistant prostate cancer; drug resistance; lncRNA
Authors: Leila Jahangiri; Tala Ishola; Perla Pucci; Ricky M Trigg; Joao Pereira; John A Williams; Megan L Cavanagh; Georgios V Gkoutos; Loukia Tsaprouni; Suzanne D Turner Journal: Cancers (Basel) Date: 2021-03-11 Impact factor: 6.639
Authors: Milad Ashrafizadeh; Mahshid Deldar Abad Paskeh; Sepideh Mirzaei; Mohammad Hossein Gholami; Ali Zarrabi; Farid Hashemi; Kiavash Hushmandi; Mehrdad Hashemi; Noushin Nabavi; Francesco Crea; Jun Ren; Daniel J Klionsky; Alan Prem Kumar; Yuzhuo Wang Journal: J Exp Clin Cancer Res Date: 2022-03-22