mTOR inhibitor everolimus reduces invasiveness of melanoma cells

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.

Three-Dimensional Migration of Human Amniotic Fluid Stem Cells Involves Mesenchymal and Amoeboid Modes and is Regulated by mTORC1

“…Whereas the crucial role of mTOR signaling for cancer cell invasion has been demonstrated in a variety of different tumor cell models, 45 , 46 , 47 , 48 , 49 , 50 the involvement of mTOR in the control of 3D migration of nontransformed cells is not well studied. In an earlier study we found that the invasion potential of primary human fibroblasts depends on mTORC1 and can be induced by hESCs, human induced‐pluripotent stem cells (hiPSCs), and hAFSCs cells via paracrine induction of mTORC1 activity.…”

Mitochondrial Metabolism in Melanoma

“…Notably, AKT1 activation is sufficient to transform noninvasive melanoma into an invasive form in vivo [80,160]. Downstream effectors of AKT1, such as the mTORC1 protein, have key effects on the metabolism of melanoma cells [5,55,161].…”

“…Because of the importance of the PI3K/AKT1 signaling axis in cancer proliferation and metabolism, treatments targeting the pathway could be promising. Everolimus, a treatment that inhibits both mTORC1 and mTORC2, has been shown to reduce the invasiveness of melanoma cells [161]. A phase I clinical trial combining the BRAF inhibitor vemurafenib and everolimus showed generally favorable results for patients with advanced cancers, along with no excessive toxicity [170].…”

Still Living Better through Chemistry: An Update on Caloric Restriction and Caloric Restriction Mimetics as Tools to Promote Health and Lifespan

“…Therefore, although CR and rapamycin both function to extend health and lifespan consistently across organisms, the impacts of these compounds are transcriptomically varied. Human melanoma cells: Lu1205, WM793 (5 nm, 24 h) [221] ↓ 3xTg-AD mice (AD model) (One dose of 0.167 µg/µL in a volume of 6 µL) [222] ↓…”

“…In some human cancers, this exerts an antiproliferative effect, inhibiting migration and angiogenesis [230], parallel to CR, AAR, and rapamycin [230]. Everolimus alone, or combined with other anticancer agents, has been shown to attenuate cancer cell growth, promote increased cell death, and increase patient survival [221,224,225,231,232]. Sabine et al [233] observed that patients with early-stage breast cancer had decreased expression of genes involved in cell cycle and proliferation, pyrimidine metabolism, and p53 signaling pathways in response to everolimus.…”