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p38β (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models
R Pascual-Serra1, D M Fernández-Aroca1, S Sabater2
1Laboratorio de Oncología, Unidad de Medicina Molecular, Centro Regional de Investigaciones Biomédicas, Universidad de Castilla-La Mancha, Unidad Asociada de Biomedicina UCLM, Unidad Asociada al CSIC, Albacete, Spain.
Background And Purpose:
Gemcitabine is an antitumour agent currently used in the treatment of several types of cancer with known properties as a radiosensitizer. p38MAPK signalling pathway has been shown to be a major determinant in the cellular response to gemcitabine in different experimental models. However, the molecular mechanism implicated in gemcitabine-associated radiosensitivity remains unknown.
Materials And Methods:
The human sarcoma cell lines A673 and HT1080, and a mouse cell line derived from a 3-methylcholanthrene induced sarcoma were used as experimental models. Modulation of p38MAPKs was performed by pharmacological approaches (SB203580) and genetic interference using lentiviral vectors coding for specific shRNAs. Viability was assessed by MTT. Gene expression was evaluated by western blot and RT-qPCR. Induction of apoptosis was monitored by caspase 3/7 activity. Response to ionizing radiation was evaluated by clonogenic assays.
Results:
Our data demonstrate that chemical inhibition of p38MAPK signalling pathway blocks gemcitabine radiosensitizing potential. Genetic interference of MAPK14 (p38α), the most abundantly expressed and best characterized p38MAPK, despite promoting resistance to gemcitabine, it does not affect its radiosensitizing potential. Interestingly, specific knockdown of MAPK11 (p38β) induces a total loss of the radiosensitivity associated to gemcitabine, as well as a marked increase in the resistance to the drug.
Conclusion:
The present work identifies p38β as a major determinant of the radiosensitizing potential of gemcitabine without implication of p38α, suggesting that p38β status should be analysed in those cases in which gemcitabine is combined with ionizing radiation.
Insights
The p38β protein is key to gemcitabine’s ability to enhance radiation therapy effectiveness. Targeting p38β could improve cancer treatment when gemcitabine is combined with radiation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Gemcitabine is an anticancer drug with radiosensitizing properties.
- The p38 mitogen-activated protein kinase (MAPK) pathway influences cellular response to gemcitabine.
- The precise mechanism of gemcitabine's radiosensitizing effect is not fully understood.
Purpose of the Study:
- To investigate the role of the p38MAPK signaling pathway in gemcitabine-induced radiosensitivity.
- To identify specific p38MAPK isoforms involved in this process.
Main Methods:
- Utilized human and mouse sarcoma cell lines.
- Modulated p38MAPK activity using pharmacological inhibitors and genetic knockdown (shRNAs).
- Assessed cell viability, gene expression, apoptosis, and radiation response using MTT assays, western blot, RT-qPCR, and clonogenic assays.
Main Results:
- Inhibiting the p38MAPK pathway abolished gemcitabine's radiosensitizing effect.
- Knockdown of MAPK14 (p38α) increased gemcitabine resistance but did not alter radiosensitivity.
- Specific knockdown of MAPK11 (p38β) completely eliminated gemcitabine's radiosensitizing potential and increased drug resistance.
Conclusions:
- p38β is identified as a critical mediator of gemcitabine's radiosensitizing effects.
- p38α is not implicated in gemcitabine's radiosensitivity.
- p38β status should be considered when combining gemcitabine with ionizing radiation in cancer therapy.
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