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Published on: July 21, 2018
MET/PKCbeta expression correlate with metastasis and inhibition is synergistic in lung cancer
Leonardo Faoro1, Gustavo M Cervantes, Benjamin D Ferguson
1Section of Hematology/Oncology, Department of Medicine, University of Chicago Pritzker School of Medicine, and University of Chicago Cancer Research Center, Chicago, IL 60637, USA.
Background:
Treatment of non-small cell lung cancer (NSCLC) remains a difficult task in oncology. Targeted inhibition of oncogenic proteins is promising. In this study, we evaluate the expression of MET and PKCbeta and in vitro effects of their inhibition using SU11274 and enzastaurin (LY317615.HCl) respectively.
Materials And Methods:
Patient samples were analyzed by immunohistochemistry for expression of PKCbeta and MET, utilizing tissue microarrays under an IRB-approved protocol. Expression of PKCbeta and MET was evaluated in cell lines by immunoblotting. Treatment with SU1174 against MET and enzastaurin against PKCbeta was performed in H1993 and H358 cell lines, and cell proliferation and downstream signaling (phosphorylation of MET, AKT, FAK, and GSK3beta) were evaluated by immunoblotting. Statistical analysis was performed using SPSS 16.0.
Results:
Expression of MET positively correlated with lymph node metastases (p=.0004), whereas PKCbeta showed no correlation (p=0.204). MET and PKCbeta expression were also strongly correlated (p<0.001). Expression of MET was observed in 5/8 cell lines (H358, H1703, A549, H1993, H2170; absent from H522, H661, or SW1573), whereas PKCbeta expression was observed in 8/8 cell lines. Cell proliferation was significantly impaired by treatment with SU11274 and enzastaurin, and their effects were synergistic in combination (CI=0.32 and 0.09). Phosphorylation of MET, FAK, AKT, and GSK3beta were strongly inhibited with both agents in combination.
Conclusions:
Concomitant inhibition of MET and PKCbeta significantly increased cytotoxicity in vitro against NSCLC, disrupting important downstream signaling pathways. Further evaluation in animal models is warranted.
Insights
Targeted inhibition of MET and PKCbeta shows promise for non-small cell lung cancer (NSCLC) treatment. Combined inhibition synergistically reduced cancer cell proliferation and disrupted key signaling pathways in vitro.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) treatment remains challenging.
- Targeted inhibition of oncogenic proteins offers a promising therapeutic strategy.
- This study investigates the expression of MET and PKCbeta in NSCLC and the effects of their inhibition.
Purpose of the Study:
- To evaluate the expression of MET and PKCbeta in NSCLC patient samples and cell lines.
- To assess the in vitro effects of inhibiting MET with SU11274 and PKCbeta with enzastaurin.
- To determine the synergistic effects of combined MET and PKCbeta inhibition on NSCLC cell proliferation and signaling.
Main Methods:
- Immunohistochemistry and immunoblotting were used to evaluate MET and PKCbeta expression in patient samples and cell lines.
- NSCLC cell lines (H1993 and H358) were treated with SU11274 (MET inhibitor) and enzastaurin (PKCbeta inhibitor).
- Cell proliferation and downstream signaling pathway phosphorylation (MET, AKT, FAK, GSK3beta) were assessed.
Main Results:
- MET expression correlated positively with lymph node metastases and strongly with PKCbeta expression.
- Both MET and PKCbeta were expressed in most NSCLC cell lines examined.
- Combined treatment with SU11274 and enzastaurin synergistically inhibited cell proliferation and key downstream signaling pathways.
Conclusions:
- Concomitant inhibition of MET and PKCbeta significantly enhances cytotoxicity against NSCLC in vitro.
- This dual inhibition disrupts critical downstream signaling pathways involved in cancer progression.
- Further investigation in preclinical animal models is warranted to explore therapeutic potential.
