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.
Highlights
Tumor cell migration and invasion that play fundamental roles in cancer metastasis are highly complicated, multistage processes with several signaling pathways and proteins involved in it
Discussion mammalian target of rapamycin (mTOR) signaling pathways mTOR—plays a key role in homeostasis, integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation, invasion, and survival [3, 4, 10]. It has been previously demonstrated [6] that treatment of melanoma cells with mTOR inhibitors: rapamycin or everolimus had a significant effect on cell cycle regulation, and in consequence, proliferation [6, 8] as their use led to a significant reduction of the number of cancer cells
As many current studies focused—in the search for effective anticancer treatment—on new capabilities of already registered drugs and their use in combination with other potential anticancer ones, we decided to examine the effect of protein kinase inhibitors—in particular the very promising mTOR inhibitor—everolimus on cell invasion and metalloproteinase activity
Summary
Tumor cell migration and invasion that play fundamental roles in cancer metastasis are highly complicated, multistage processes with several signaling pathways and proteins involved in it. MTORC1 complex regulates cell growth, proliferation, migration, and invasion [1, 2]; overexpression of downstream mTORC1 effectors (p70-S6K1 and 4E-BP1) leads to poor cancer prognosis [2]. The effects of the combined use of rapalogs with other anticancer agents or rapalogs alone are under investigation in several human cancers, such as brain, breast, and other solid tumors [5]
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