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Joint CB1 and NGF Receptor Activation Suppresses TRPM8 Activation in Etoposide-Resistant Retinoblastoma Cells

Szymon Ludwiczak1, Jacqueline Reinhard2, Peter S Reinach3

  • 1Department of Ophthalmology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.

International Journal of Molecular Sciences
|February 10, 2024
PubMed

Insights

Retinoblastoma cells resistant to etoposide show increased cannabinoid receptor 1 (CNR1) expression. This may suppress TRPM8 expression, impacting calcium signaling and drug resistance in eye tumors.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Retinoblastoma (RB) is the most common primary eye tumor in children.
  • Etoposide is a key treatment, but RB cells can develop resistance.
  • Understanding resistance mechanisms is crucial for improving therapeutic outcomes.

Purpose of the Study:

  • To investigate the role of calcium (Ca2+) signaling in etoposide resistance in retinoblastoma.
  • To compare receptor-mediated Ca2+ signaling in etoposide-sensitive and -insensitive RB cells.
  • To explore the relationship between gene expression of cannabinoid receptor 1 (CNR1) and transient receptor potential melastatin 8 (TRPM8) in RB resistance.

Main Methods:

  • Utilized fluorescence calcium imaging to measure Ca2+ transients.
  • Employed semi-quantitative RT-qPCR to analyze gene expression levels of CNR1 and TRPM8.
  • Assessed cell viability using trypan blue dye exclusion in WERI-Rb1 (sensitive) and WERI-ETOR (insensitive) cell lines.

Main Results:

  • NGF induced larger Ca2+ rises in WERI-ETOR cells compared to WERI-Rb1 cells.
  • Etopsoside-insensitive WERI-ETOR cells exhibited higher CNR1 gene expression than WERI-Rb1 cells.
  • Pretreatment with NGF and WIN55,212-2 led to suppressed TRPM8 expression and blocked icilin-induced Ca2+ transients specifically in WERI-ETOR cells.

Conclusions:

  • Increased CNR1 gene expression in retinoblastoma cells may be linked to etoposide insensitivity.
  • Crosstalk between CNR1 and TRPM8 signaling pathways appears to play a role in RB etoposide resistance.
  • These findings suggest novel therapeutic targets for overcoming drug resistance in retinoblastoma.
Keywords:
Ca2+ signalingcannabinoid receptor 1chemotherapy resistanceetoposidenerve growth factorretinoblastomatransient receptor potential channel melastatin 8transient receptor potential channel vanilloid 1

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