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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
mTOR inhibitor everolimus reduces invasiveness of melanoma cells
Dorota Ciołczyk-Wierzbicka1, Dorota Gil2, Marta Zarzycka2
1Chair of Medical Biochemistry, Jagiellonian University Medical College, ul. Kopernika 7, 31-034, Kraków, Poland. mbciolcz@cyf-kr.edu.pl.
Abstract:
The mammalian target of rapamycin (mTOR) plays a key role in several cellular processes: proliferation, survival, invasion, and angiogenesis, and therefore, controls cell behavior both in health and in disease. Dysregulation of the mTOR signaling is involved in some of the cancer hallmarks, and thus the mTOR pathway is an important target for the development of a new anticancer therapy. The object of this study is recognition of the possible role of mTOR kinase inhibitors-everolimus single and in combination with selected downstream protein kinases inhibitors: LY294002 (PI3 K), U0126 (ERK1/2), GDC-0879 (B-RAF), AS-703026 (MEK), MK-2206 (AKT), PLX-4032 (B-RRAF) in cell invasion in malignant melanoma. Treatment of melanoma cells with everolimus led to a significant decrease in the level of both phosphorylated: mTOR (Ser2448) and mTOR (Ser2481) as well as their downstream effectors. The use of protein kinase inhibitors produced a significant decrease in metalloproteinases (MMPs) activity, as well as diminished invasion, especially when used in combination. The best results in the inhibition of both MMPs and cell invasiveness were obtained for the combination of an mTOR inhibitor- everolimus with a B-RAF inhibitor-PLX-4032. Slightly less profound reduction of invasiveness was obtained for the combinations of an mTOR inhibitor-everolimus with ERK1/2 inhibitor-U126 or MEK inhibitor-AS-703026 and in the case of MMPs activity decrease for PI3 K inhibitor-LY294002 and AKT inhibitor-MK-2206. The simultaneous use of everolimus or another new generation rapalog with selected inhibitors of crucial signaling kinases seems to be a promising concept in cancer treatment.
Insights
Everolimus, an mTOR inhibitor, combined with other kinase inhibitors, significantly reduced malignant melanoma cell invasion and metalloproteinases activity. The combination of everolimus and PLX-4032 (B-RAF inhibitor) showed the best results in inhibiting melanoma invasion.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The mammalian target of rapamycin (mTOR) pathway regulates critical cellular functions like proliferation and survival.
- Dysregulation of mTOR signaling is implicated in cancer development, making it a therapeutic target.
- Malignant melanoma invasion is a complex process involving multiple signaling pathways.
Purpose of the Study:
- To investigate the role of everolimus, an mTOR kinase inhibitor, alone and in combination with downstream protein kinase inhibitors.
- To evaluate the efficacy of these combinations in inhibiting cell invasion in malignant melanoma.
- To identify the most effective combination for reducing melanoma cell invasiveness and metalloproteinases activity.
Main Methods:
- Treatment of melanoma cells with everolimus and various protein kinase inhibitors (LY294002, U0126, GDC-0879, AS-703026, MK-2206, PLX-4032).
- Assessment of phosphorylated mTOR levels (Ser2448 and Ser2481) and downstream effectors.
- Measurement of metalloproteinases (MMPs) activity and evaluation of cell invasiveness.
- Comparative analysis of single-agent versus combination therapy effects.
Main Results:
- Everolimus treatment significantly decreased phosphorylated mTOR levels and its downstream effectors.
- Combinations of everolimus with protein kinase inhibitors markedly reduced MMPs activity and cell invasion.
- The combination of everolimus with PLX-4032 (B-RAF inhibitor) demonstrated the most potent inhibition of MMPs and melanoma cell invasiveness.
- Other combinations, such as everolimus with U0126 (ERK1/2 inhibitor) or AS-703026 (MEK inhibitor), also showed significant reductions in invasiveness.
Conclusions:
- Simultaneous inhibition of mTOR and specific downstream kinases is a promising strategy for treating malignant melanoma.
- Combination therapy involving everolimus and B-RAF inhibitors like PLX-4032 offers a potent approach to combat melanoma invasion.
- Targeting key signaling kinases in combination with mTOR inhibitors warrants further investigation for novel cancer therapeutics.
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