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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Src-Induced cisplatin resistance mediated by cell-to-cell communication
Elizabeth Peterson-Roth1, Cathleen M Brdlik, Peter M Glazer
1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Cancer Research
|April 9, 2009
Summary
Activated src oncogene signaling enhances cancer cell survival by disrupting gap junction communication, conferring cisplatin resistance to neighboring cells. This novel pathway offers potential therapeutic targets for overcoming chemotherapy resistance.
Area of Science:
- Cell Biology
- Oncology
- Molecular Pharmacology
Background:
- Cisplatin chemotherapy induces cancer cell death, but resistance mechanisms limit its efficacy.
- Cell-to-cell communication via gap junctions influences cellular responses to drugs.
- The role of oncogene-activated signaling in mediating chemoresistance through intercellular communication is not fully understood.
Purpose of the Study:
- To investigate the role of activated src signaling in cisplatin-induced cell death and survival.
- To determine if src activity can influence the survival of neighboring cells in response to cisplatin.
- To elucidate the molecular mechanisms underlying src-mediated chemoresistance.
Main Methods:
- Utilized mixed cell populations to study intercellular effects of src activity.
- Investigated tyrosine phosphorylation of connexin 43 (a gap junction protein) by activated src.
- Employed src kinase inhibitors and small interfering RNA (siRNA) for src knockdown.
- Assessed the impact of forced connexin 43 up-regulation on cell survival.
Main Results:
- Activated src phosphorylates connexin 43, reducing gap junction communication and increasing cell survival against cisplatin.
- src activity in one cell confers cisplatin resistance to adjacent cells lacking src activity.
- This trans-acting effect is blocked by src inhibitors or knockdown and counteracted by increased connexin 43 levels.
Conclusions:
- Activated src signaling confers cisplatin resistance through intercellular communication, impacting neighboring cells.
- This oncogene-driven pathway represents a novel mechanism of chemotherapy resistance.
- Targeting this src-connexin 43 pathway may offer new therapeutic strategies against cisplatin-resistant cancers.
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