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G protein-coupled receptor kinase 5 modifies cancer cell resistance to paclitaxel

Joann Lagman1, Paula Sayegh1, Christina S Lee1

  • 1Roseman University of Health Sciences School of Pharmacy, 11 Sunset Way, Henderson, NV, 89014, USA.

Molecular and Cellular Biochemistry
|August 1, 2019
PubMed

Insights

Reduced G protein-coupled receptor kinase 5 (GRK5) levels increase cancer cell sensitivity to paclitaxel by affecting histone deacetylase 6 (HDAC6) activity and α-tubulin acetylation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • G protein-coupled receptor kinases (GRKs) regulate G protein-coupled receptors (GPCRs) and other signaling pathways.
  • GRKs influence diverse cellular functions beyond GPCR regulation.

Purpose of the Study:

  • To investigate the role of GRK5 in paclitaxel sensitivity in cancer cells.
  • To elucidate the molecular mechanism linking GRK5, HDAC6, and paclitaxel response.

Main Methods:

  • Utilized cervical and breast cancer cell lines (HeLa, MDA MB 231) with manipulated GRK5 expression.
  • Assessed paclitaxel-induced apoptosis and α-tubulin acetylation levels.
  • Examined the interaction and phosphorylation of HDAC6 by GRK5 in vitro and in cellulo.

Main Results:

  • Reduced GRK5 expression in cancer cells enhanced sensitivity to paclitaxel-induced apoptosis.
  • Low GRK5 levels correlated with decreased histone deacetylase 6 (HDAC6) activity and increased α-tubulin acetylation.
  • Demonstrated a direct interaction between GRK5 and HDAC6, with GRK5 phosphorylating HDAC6 at Ser-21 to enhance its deacetylase activity.

Conclusions:

  • The GRK5-HDAC6 signaling complex plays a critical role in regulating paclitaxel sensitivity in cancer cells.
  • GRK5-mediated phosphorylation of HDAC6 contributes to paclitaxel resistance.
  • Targeting the GRK5-HDAC6 interaction may represent a novel therapeutic strategy for enhancing paclitaxel efficacy in cancer treatment.
Keywords:
AcetylationCancerG protein-coupled receptor kinaseHistone deacetylasePaclitaxel

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