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Published on: August 23, 2018
Focal adhesion alterations in G0-positive melanoma cells
Alexandra R Esimbekova1, Nadezhda V Palkina1, Ivan S Zinchenko1
1Department of Pathophysiology, Krasnoyarsk State Medical University, Krasnoyarsk, Russia.
Background:
Melanoma is a highly heterogeneous malignant tumor that exhibits various forms of drug resistance. Recently, reversal transition of cancer cells to the G0 phase of the cell cycle under the influence of therapeutic drugs has been identified as an event associated with tumor dissemination. In the present study, we investigated the ability of chemotherapeutic agent dacarbazine to induce a transition of melanoma cells to the G0 phase as a mechanism of chemoresistance.
Methods:
We used the flow cytometry to analyze cell distribution within cell cycle phases after dacarbazine treatment as well as to identifyG0 -positive cells population. Transcriptome profiling was provided to determine genes associated with dacarbazine resistance. We evaluated the activity of β-galactosidase in cells treated with dacarbazine by substrate hydrolysis. Cell adhesion strength was measured by centrifugal assay application with subsequent staining of adhesive cells with Ki-67 monoclonal antibodies. Ability of melanoma cells to metabolize dacarbazine was determined by expressional analysis of CYP1A1, CYP1A2, CYP2E1 followed by CYP1A1 protein level evaluation by the ELISA method.
Results:
The present study determined that dacarbazine treatment of melanoma cells could induce an increase in the percentage of cells in G0 phase without alterations of β-galactosidase positive cells which corresponded to the fraction of the senescent cells. Transcriptomic profiling of cells under dacarbazine induction of G0 -positive cells percentage revealed that 'VEGFA-VEGFR2 signaling pathway' and 'Cell cycle' signaling were mostly enriched by dysregulated genes. 'Focal adhesion' signaling was also found to be triggered by dacarbazine. In melanoma cells treated with dacarbazine, an increase in G0 -positive cells among adherent cells was found.
Conclusions:
Dacarbazine induces the alteration in a percentage of melanoma cells residing in G0 phase of a cell cycle. The altered adhesive phenotype of cancer cells under transition in the G0 phase may refer to a specific intercellular communication pattern of quiescent/senescent cancer cells.
Insights
Dacarbazine treatment increases the percentage of melanoma cells entering the G0 phase, a mechanism linked to chemoresistance. This transition affects cell adhesion and may indicate altered intercellular communication in quiescent cancer cells.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Melanoma exhibits significant heterogeneity and drug resistance.
- Therapeutic drugs can induce cancer cell transition to the G0 phase, potentially leading to tumor dissemination.
- Understanding dacarbazine's effect on melanoma cell cycle is crucial for chemoresistance research.
Purpose of the Study:
- To investigate dacarbazine's ability to induce G0 phase transition in melanoma cells.
- To identify mechanisms of chemoresistance related to dacarbazine treatment.
- To analyze gene expression and cellular changes associated with dacarbazine-induced G0 phase.
Main Methods:
- Flow cytometry to analyze cell cycle distribution and G0-positive cells.
- Transcriptome profiling to identify genes related to dacarbazine resistance.
- Assays for beta-galactosidase activity, cell adhesion, and dacarbazine metabolism (CYP enzymes).
Main Results:
- Dacarbazine treatment increased the percentage of melanoma cells in the G0 phase without affecting senescent cells.
- Transcriptomic analysis revealed enrichment of 'VEGFA-VEGFR2 signaling pathway' and 'Cell cycle' signaling.
- Dacarbazine triggered 'Focal adhesion' signaling and increased G0-positive cells among adherent melanoma cells.
Conclusions:
- Dacarbazine alters the percentage of melanoma cells in the G0 phase, contributing to chemoresistance.
- The altered adhesive phenotype in G0-phase melanoma cells suggests a unique intercellular communication pattern for quiescent/senescent cells.
