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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Adenovirus-mediated TA-p73beta gene transfer increases chemosensitivity of human malignant melanomas
1Department of Vectorology and Experimental Gene Therapy, University of Rostock, Schillingallee 70, Rostock, 18055, Germany.
Abstract:
Malignant melanoma is the most aggressive form of skin cancer and has proven to be highly resistant to conventional chemotherapy. Intriguingly, the p53 tumor suppressor, a main mediator of chemoresistance in other tumor types, is rarely mutated in melanoma. However, we have previously shown that anti-apoptotic isoforms of p73 (deltaTA-p73), another member of the p53 family, are overexpressed in metastatic melanomas. DeltaTA-p73 can oppose the pro-apoptotic functions of p53 and full length p73, and thus it could contribute to melanoma chemoresistance. In this study, we use an efficient adenoviral-based gene transfer approach to introduce a transcriptionally active form of p73 (TA-p73beta) in melanoma cells, with the objective of overcoming drug resistance. Interestingly, TA-p73beta significantly sensitized 5 out of 7 aggressive melanoma cell lines to the standard therapeutic agents adriamycin and cisplatin. More importantly, TA-p73beta displayed a synergistic effect in vivo allowing adriamycin or cisplatin to block melanoma cell growth in mouse xenograft models (p < 0.05). In summary, our data show that Ad-mediated TA-p73beta gene expression can markedly sensitize a subset of melanoma cell lines to adriamycin and cisplatin in vitro and in vivo, suggesting a new chemosensitization strategy for malignant melanomas.
Insights
Introducing TA-p73beta via gene therapy sensitized melanoma cells to chemotherapy. This approach effectively blocked tumor growth in preclinical models, offering a novel strategy against aggressive skin cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Malignant melanoma exhibits high chemoresistance, with p53 rarely mutated.
- Overexpressed anti-apoptotic deltaTA-p73 isoforms in metastatic melanomas may drive chemoresistance.
- DeltaTA-p73 antagonizes pro-apoptotic functions of p53 and full-length p73.
Purpose of the Study:
- To investigate if introducing transcriptionally active p73 (TA-p73beta) can overcome drug resistance in melanoma.
- To evaluate the efficacy of TA-p73beta in sensitizing melanoma cells to chemotherapy agents.
Main Methods:
- Adenoviral gene transfer was used to deliver TA-p73beta into melanoma cells.
- Sensitization to adriamycin and cisplatin was assessed in vitro across multiple melanoma cell lines.
- Efficacy was further evaluated in vivo using mouse xenograft models.
Main Results:
- TA-p73beta significantly sensitized 5 out of 7 aggressive melanoma cell lines to adriamycin and cisplatin.
- In vivo studies demonstrated a synergistic effect, where TA-p73beta enhanced the ability of chemotherapy to inhibit melanoma tumor growth.
- Adenovirus-mediated TA-p73beta expression showed significant results in blocking melanoma cell proliferation.
Conclusions:
- Adenovirus-mediated TA-p73beta gene expression offers a promising strategy for chemosensitization in a subset of malignant melanomas.
- This approach shows potential for overcoming chemoresistance in aggressive skin cancers.
- The findings suggest a novel therapeutic avenue for treating drug-resistant melanoma.
