mTOR inhibitor everolimus reduces invasiveness of melanoma cells
Tóm tắt
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.
Tài liệu tham khảo
Zhou H, Huang S. Role of mTOR signaling in tumor cell motility invasion metastasis. Curr Protein Pept Sci. 2011;12(1):30–42.
Kim JO, Kim KH, Song IS, et al. Potentiation of the anticancer effects of everolimus using a dual mTORC1/2 inhibitor in hepatocellular carcinoma cells. Oncotarget. 2017;8(2):2936–48.
Conciatori F, Ciuffreda L, Bazzichetto Ch, et al. mTOR cross-talk in cancer and potential for combination therapy. Cancers. 2018;10(1):23. https://doi.org/10.3390/cancers10010023.
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–93. https://doi.org/10.1016/j.cell.2012.03.017.
Watanabe R, Wei L, Huang J. mTOR signaling, function, novel inhibitors, and therapeutic targets. J Nucl Med. 2011;52(4):497–500.
Ciołczyk-Wierzbicka D, Gil D, Laidler P. Treatment of melanoma with selected inhibitors of signaling kinases effectively reduces proliferation and induces expression of cell cycle inhibitors. Med Oncol. 2018;35(1):7.
Ciołczyk-Wierzbicka D, Laidler P. The inhibition of invasion of human melanoma cells through N-cadherin knockdown. Med Oncol. 2018;35(4):42.
Ciołczyk-Wierzbicka D, Zarzycka M, Gil D, Laidler P. mTOR inhibitor everolimus-induced apoptosis in melanoma cells. J Cell Commun Signal. 2019;9:9. https://doi.org/10.1007/s12079-019-00510-0.
Ciołczyk-Wierzbicka D, Gil D, Laidler P. The inhibition of cell proliferation using silencing of N-cadherin gene by siRNA process in human melanoma cell lines. Curr Med Chem. 2012;19(1):145–51.
Cheng K, Hao M. Mammalian target of rapamycin (mTOR) regulates transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition via decreased pyruvate kinase M2 (PKM2) expression in cervical cancer cells. Med Sci Monitor: Int Med J Exp Clin Res. 2017;23:2017–28.
Walker N, Belloli E, Stuckey L, et al. Mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 as key signaling intermediates in mesenchymal cell activation. J Biol Chem. 2016;291(12):6262–71. https://doi.org/10.1074/jbc.M115.672170.
Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci. 2012;13(2):1886–918.
Ge Y, Chen J. Mammalian target of rapamycin (mTOR) signaling network in skeletal myogenesis. J Biol Chem. 2012;287(52):43928–35. https://doi.org/10.1074/jbc.R112.406942.
Schreiber KH, Ortiz D, Academia EC, Anies AC, Liao CY, Kennedy BK. Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell. 2015;14(2):265–73.
Watari K, Nishitani A, Shibata, et al. Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma. Oncotarget. 2016;7(30):47403–17. https://doi.org/10.18632/oncotarget.10161.
Chen B, Tan Z, Gao J, et al. Hyperphosphorylation of ribosomal protein S6 predicts unfavorable clinical survival in non-small cell lung cancer. J Exp Clin Cancer Res. 2015;34:126.
Wang JY, Fan H. P70S6 kinase phosphorylation: a new site to assess pharmacodynamy of sirolimus. Chin Med J (Engl). 2015;128(5):664–9. https://doi.org/10.4103/0366-6999.151670.
Du L, Li X, Zhen L, et al. Everolimus inhibits breast cancer cell growth through PI3 K/AKT/mTOR signaling pathway. Mol Med Rep. 2018;17(5):7163–9.
Lin T, Leung C, Nguyen KT, Figlin RA. Mammalian target of rapamycin (mTOR) inhibitors in solid tumors. Clin Pharm. 2016. https://doi.org/10.1211/CP.2016.20200813.
Aguilera JV, Rao RD, Allred JB, et al. Phase II study of everolimus in metastatic malignant melanoma (NCCTG-N0377, Alliance). Oncologist. 2018;23(8):887. https://doi.org/10.1634/theoncologist.2018-0100e94.
Weeber F, Cirkel GA, Hoogstraat M, et al. Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study. Oncotarget. 2017;8(33):55582–92.
Ruzzolini J, Peppicelli S, Andreucci E, et al. Everolimus selectively targets vemurafenib resistant BRAFV600E melanoma cells adapted to low pH. Cancer Lett. 2017;408(1):43–54.
Yang F, Gao J-Y, Chen H, Du Z-H, Zhang X-Q, Gao W. Targeted inhibition of the phosphoinositide 3-kinase impairs cell proliferation, survival, and invasion in colon cancer. OncoTargets ther. 2017;10:4413–22. https://doi.org/10.2147/OTT.S145601.
Li X, Dai D, Chen B, Tang H, Xie X, Wei W. Efficacy of PI3 K/AKT/mTOR pathway inhibitors for the treatment of advanced solid cancers: a literature-based meta-analysis of 46 randomised control trials. PLoS One. 2018;13(2):e0192464. https://doi.org/10.1371/journal.pone.0192464.
Sathe A, Chalaud G, Oppolzer I, et al. Parallel PI3 K, AKT and mTOR inhibition is required to control feedback loops that limit tumor therapy. PLoS One. 2018;13(1):e0190854.
Sathe A, Nawroth R. Targeting the PI3 K/AKT/mTOR pathway in bladder cancer. Methods Mol Biol. 2018;1655:335–50.