Single-cell Transcriptome Analyses Reveal Molecular Signals to Intrinsic and Acquired Paclitaxel Resistance in Esophageal Squamous Cancer Cells

Cancer Lett. 2018 Apr 28;420:156-167. doi: 10.1016/j.canlet.2018.01.059. Epub 2018 Feb 1.

Abstract

Paclitaxel is widely used in the combination chemotherapy for many cancers including esophageal squamous cell carcinoma (ESCC). However, the paclitaxel resistance occurs frequently in treating ESCC and the mechanism is not fully understood yet. The heterogeneity of gene expression within the drug-resistant cancer cells may be one of the major factors contributing to its resistance. In the present study, we successfully induced paclitaxel resistance in ESCC cell line KYSE-30 through low dose and long-term treatment of paclitaxel. Gene expression profiles were measured utilizing population RNA-seq and single-cell RNA-seq (scRNA-seq). 37 single cells from KYSE-30 cells and 73 single cells from paclitaxel resistant KYSE-30 cells (Taxol-R) were subjected to scRNA-seq. Weighted gene co-expression network analysis (WGCNA) of scRNA-seq data revealed two major subpopulations in both KYSE-30 and Taxol-R cancer cells. Two subpopulations based on the KRT19 expression levels in KYSE-30 cells exhibited different paclitaxel sensitivity, suggesting the existence of an intrinsic paclitaxel resistance in KYSE-30 cells. In addition, the Taxol-R cells that acquired the resistance to paclitaxel through induction were characterized with higher expressions of proteasomes but a lower expression of HIF-1 signaling genes. Furthermore, we showed that carfilzomib (CFZ), a proteasome inhibitor, could attenuate the paclitaxel resistance in Taxol-R cancer cells through activating the HIF-1 signaling. Our new finding may pave a way leading to an improvement in the treatment on cancers including ESCC by combining CFZ with paclitaxel as a novel approach for cancer therapy.

Keywords: Acquired paclitaxel resistance; Esophageal squamous cancer; HIF-1 signaling; Intrinsic paclitaxel resistance; Proteasome; Single-cell RNA-seq.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Esophageal Neoplasms / drug therapy
  • Esophageal Neoplasms / genetics*
  • Esophageal Squamous Cell Carcinoma / drug therapy
  • Esophageal Squamous Cell Carcinoma / genetics*
  • Female
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Regulatory Networks / drug effects*
  • Humans
  • Mice
  • Neoplasm Transplantation
  • Paclitaxel / pharmacology*
  • Proteasome Endopeptidase Complex / genetics
  • Sequence Analysis, RNA / methods
  • Single-Cell Analysis / methods*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Proteasome Endopeptidase Complex
  • Paclitaxel