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Published on: October 2, 2015
Targeting ROR1 in combination with pemetrexed in malignant mesothelioma cells
Noriko Miyake1, Nobuaki Ochi2, Hiromichi Yamane2
1General Medical Center Research Unit, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama 700-8505, Japan.
Objective:
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in a subset of malignant cells. However, it remains unknown whether ROR1 is targetable in malignant mesothelioma (MM). Therefore, in this study, we investigated the effects of ROR1 inhibition in mesothelioma cells.
Materials And Methods:
Growth inhibition, colony formation, apoptosis, and mRNA/protein levels using siRNA-transfected MM cells were evaluated. Cluster analysis using Gene Expression Omnibus repository of transcriptomic information was also performed.
Results:
Our results indicated that in three (H2052, H2452, and MESO-1) among four MM cell lines, ROR1 inhibition had anti-proliferative and apoptotic effects and suppressed the activation of AKT and STAT3. Although growth inhibition by siROR1 was minimal in another mesothelioma cell line (H28), colony formation was significantly suppressed. Microarray, quantitative polymerase chain reaction, and Western blot analyses showed that there were differences in the suppression of mRNA and proteins between H2452 and H28 cells transfected with siROR1 compared with those transfected with control siRNA. Cluster analysis further showed that MM tumors had relatively high ROR1 expression, although the cluster in them was different from that in MM cell lines. Thymidylate synthase, a target of pemetrexed, was downregulated in H2452 cells transfected with siROR1. Accordingly, a combination of pemetrexed with siROR1 was found to be effective in the three MM cell lines we studied.
Conclusion:
Our findings may provide novel therapeutic insight into the treatment of advanced MM.
Insights
Inhibiting Receptor tyrosine kinase-like orphan receptor 1 (ROR1) shows anti-cancer effects in malignant mesothelioma (MM) cells. Combination therapy with ROR1 inhibition and pemetrexed offers a promising treatment strategy for advanced MM.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is frequently overexpressed in various cancers.
- The therapeutic potential of targeting ROR1 in malignant mesothelioma (MM) remains largely unexplored.
Purpose of the Study:
- To investigate the efficacy of ROR1 inhibition as a therapeutic strategy in MM.
- To evaluate the impact of ROR1 targeting on MM cell proliferation, apoptosis, and key signaling pathways.
Main Methods:
- Utilized siRNA to inhibit ROR1 expression in MM cell lines.
- Assessed effects on cell growth, colony formation, and apoptosis.
- Analyzed mRNA and protein expression levels of ROR1 and downstream targets.
- Performed cluster analysis on transcriptomic data from the Gene Expression Omnibus repository.
Main Results:
- ROR1 inhibition demonstrated anti-proliferative and apoptotic effects in three out of four MM cell lines, suppressing AKT and STAT3 activation.
- While growth inhibition was minimal in one cell line (H28), colony formation was significantly reduced.
- Downregulation of thymidylate synthase, a pemetrexed target, was observed in ROR1-inhibited cells.
- A combination of pemetrexed and ROR1 inhibition proved effective in multiple MM cell lines.
Conclusions:
- ROR1 is a potential therapeutic target in malignant mesothelioma.
- Targeting ROR1, particularly in combination with pemetrexed, offers a novel therapeutic avenue for advanced MM treatment.
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