A comprehensive gene expression profile analysis of prostate cancer cells resistant to paclitaxel and the potent target to reverse resistance

Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221129854. doi: 10.1177/09603271221129854.

Abstract

Background: Paclitaxel resistance is the major clinical obstacle in the chemotherapy of prostate cancer (PCa), but the resistant mechanism is less investigated.Purpose: To establish two paclitaxel-resistant PCa cells, provide a comprehensive gene expression profile analysis of resistant cells and the potential target to reverse resistance.Methods: Two Paclitaxel-resistant PCa cells (PC3/PR, LNcap/PR) were established by gradually increasing drug concentration. MTT and transwell assays were performed to detect drug sensitivity, cell proliferation and migration abilities. RNA-Sequencing (RNA-seq) and bioinformatic analyses were performed to identify abnormally expressed genes (AEGs) in resistant cells, and annotate the biological functions of AEGs. The role of the candidate AEG, TLR-4, on the resistant phenotypes was further investigated.Results: The resistance index of resistant cells was 2-3, and they showed a slower proliferation and increased migration ability. 4741 AEGs were screened out (Log2fold change absolute: log2FC(abs) > 1) in the resistant cells, and they were enriched in 2'-5'-oligoadenylate synthetase activity and chemical carcinogenesis. A number of AEGs, CCND2, IGFBP3, FOS, SHH, ZEB2, and members of FGF, FGFR and WNT families were also identified to be involved in cancer- and resistant phenotype-related processes. Finally, TLR-4 was validated significantly increased in resistant cells, and knockdown of TLR-4 increased drug-sensitivity, inhibited the proliferation and migration abilities.Conclusions: The study provided a comprehensive gene expression profile of paclitaxel-resistant PCa cells, and TLR-4 could be a potential target to reverse paclitaxel resistance.

Keywords: Prostate cancer; RNA-Seq; TLR-4; paclitaxel; resistance.

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / metabolism
  • Antineoplastic Agents, Phytogenic* / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Paclitaxel* / pharmacology
  • Paclitaxel* / therapeutic use
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms* / genetics
  • Prostatic Neoplasms* / metabolism
  • RNA-Seq
  • Toll-Like Receptor 4 / genetics
  • Transcriptome

Substances

  • Antineoplastic Agents, Phytogenic
  • Toll-Like Receptor 4
  • 2',5'-Oligoadenylate Synthetase
  • Paclitaxel