The role of the MAD2-TLR4-MyD88 axis in paclitaxel resistance in ovarian cancer

PLoS One. 2020 Dec 28;15(12):e0243715. doi: 10.1371/journal.pone.0243715. eCollection 2020.

Abstract

Despite the use of front-line anticancer drugs such as paclitaxel for ovarian cancer treatment, mortality rates have remained almost unchanged for the past three decades and the majority of patients will develop recurrent chemoresistant disease which remains largely untreatable. Overcoming chemoresistance or preventing its onset in the first instance remains one of the major challenges for ovarian cancer research. In this study, we demonstrate a key link between senescence and inflammation and how this complex network involving the biomarkers MAD2, TLR4 and MyD88 drives paclitaxel resistance in ovarian cancer. This was investigated using siRNA knockdown of MAD2, TLR4 and MyD88 in two ovarian cancer cell lines, A2780 and SKOV-3 cells and overexpression of MyD88 in A2780 cells. Interestingly, siRNA knockdown of MAD2 led to a significant increase in TLR4 gene expression, this was coupled with the development of a highly paclitaxel-resistant cell phenotype. Additionally, siRNA knockdown of MAD2 or TLR4 in the serous ovarian cell model OVCAR-3 resulted in a significant increase in TLR4 or MAD2 expression respectively. Microarray analysis of SKOV-3 cells following knockdown of TLR4 or MAD2 highlighted a number of significantly altered biological processes including EMT, complement, coagulation, proliferation and survival, ECM remodelling, olfactory receptor signalling, ErbB signalling, DNA packaging, Insulin-like growth factor signalling, ion transport and alteration of components of the cytoskeleton. Cross comparison of the microarray data sets identified 7 overlapping genes including MMP13, ACTBL2, AMTN, PLXDC2, LYZL1, CCBE1 and CKS2. These results demonstrate an important link between these biomarkers, which to our knowledge has never before been shown in ovarian cancer. In the future, we hope that triaging patients into alterative treatment groups based on the expression of these three biomarkers or therapeutic targeting of the mechanisms they are involved in will lead to improvements in patient outcome and prevent the development of chemoresistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Biomarkers, Tumor / genetics*
  • Cell Line, Tumor
  • Cellular Senescence / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Mad2 Proteins / genetics
  • Myeloid Differentiation Factor 88 / genetics
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Paclitaxel / pharmacology*
  • Paclitaxel / therapeutic use
  • RNA, Small Interfering / metabolism
  • Toll-Like Receptor 4 / genetics

Substances

  • Antineoplastic Agents, Phytogenic
  • Biomarkers, Tumor
  • MAD2L1 protein, human
  • MYD88 protein, human
  • Mad2 Proteins
  • Myeloid Differentiation Factor 88
  • RNA, Small Interfering
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Paclitaxel

Grants and funding

NO - This research was supported by a research grant from the Royal City of Dublin Hospital Trust, the Emer Casey Foundation, SOCK and the Irish Ladies Golf Union. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.