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Maspin suppresses survival of lung cancer cells through modulation of Akt pathway
1Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Purpose:
Maspin is a tumor suppressor protein that has been reported to stimulate the cell death of cancer and inhibit the metastasis of cancer. The present study aimed to explore the survival pathway by which maspin modulates the resistance of human lung cancer cells to chemotherapeutic drugs, and the consequences of maspin gene therapy in an animal model.
Materials And Methods:
NCI-H157 and A549 cells were transfected with either a mock vector (pCMVTaq4C), maspin (pCMV-maspin), siControl or siMaspin. RT-PCR and Western blot analysis were performed to study the expressions of survival proteins in lung cancer. cDNA microarray analysis was carried out to compare the maspin-modulated gene expression between the xenograft tumors derived from the lung cancer cells that were stably transfected with pCMVTaq4C or pCMV-maspin. Maspin gene therapy was performed by intra-tumoral injections of pCMVTaq4C or pCMV-maspin into the pre-established subcutaneous tumors in nude mice.
Results:
Maspin significantly decreased the survival to doxorubicin and etoposide, whereas did not affect the survival to cisplatin in the NCI-H157 cells. Interestingly, transfection with a maspin plasmid resulted in a significant reduction of the phosphorylation of Akt in the NCI-H157 cells, whereas knockdown of maspin increased the phosphorylation of Akt in the A549 cells. Microarray analysis of the xenograft tumors revealed a specific gene expression profile, demonstrating that maspin is associated with the differential expressions of PTEN and IGF2R. Direct transfer of pCMV-maspin into the tumor significantly retarded the tumor growth in the animal experiments (p=0.0048).
Conclusion:
Lung cancer cells lacking maspin could be resistant to chemotherapeutic drugs such as doxorubicin or etoposide, at least in part by maintaining Akt phosphorylation.
Insights
Maspin suppresses lung cancer cell survival to chemotherapy by inhibiting Akt phosphorylation. Maspin gene therapy effectively reduced tumor growth in animal models, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Maspin is a tumor suppressor protein involved in cancer cell death and metastasis inhibition.
- Understanding maspin's role in chemoresistance is crucial for developing effective lung cancer treatments.
Purpose of the Study:
- To investigate how maspin influences human lung cancer cell resistance to chemotherapy.
- To evaluate the therapeutic potential of maspin gene therapy in a preclinical animal model.
Main Methods:
- Lung cancer cell lines (NCI-H157, A549) were transfected with maspin or control vectors/siRNA.
- Gene and protein expression (RT-PCR, Western blot, microarray) and Akt phosphorylation were analyzed.
- Maspin gene therapy was administered via intratumoral injection in nude mice xenografts.
Main Results:
- Maspin reduced NCI-H157 cell survival to doxorubicin and etoposide, correlating with decreased Akt phosphorylation.
- Maspin knockdown in A549 cells increased Akt phosphorylation.
- Microarray analysis revealed maspin's association with PTEN and IGF2R gene expression.
- Intratumoral maspin gene transfer significantly inhibited tumor growth in vivo.
Conclusions:
- Lung cancer cells lacking maspin may develop resistance to certain chemotherapies, partly via sustained Akt phosphorylation.
- Maspin plays a critical role in modulating chemoresistance pathways in lung cancer.
- Maspin gene therapy demonstrates efficacy in reducing tumor growth, suggesting its therapeutic value.
