Ciołczyk-Wierzbicka Dorota, Zarzycka Marta, Gil Dorota, Laidler Piotr
Medical Biochemistry, Jagiellonian University Medical College, ul. Kopernika 7, 31-034, Kraków, Poland.
J Cell Commun Signal. 2019 Sep;13(3):357-368. doi: 10.1007/s12079-019-00510-0. Epub 2019 Mar 8.
Melanoma is the most aggressive, therapy-resistant skin cancer. The mammalian target of rapamycin (mTOR), the serine/threonine kinase which integrates both intracellular and extracellular signals, plays a crucial role in coordinating the balance between the growth and death of cells. The object of this study is a comparison of the influence of mTOR inhibitor everolimus in the concentration range between 20 nM and 10 μM, used individually and in combination with selected downstream protein kinases inhibitors: LY294002 (PI3K), U0126 (ERK1/2), AS-703026 (MEK) and MK-2206 (AKT) on the expression of pro-survival proteins: p-Bcl-2 (S70), p-Bcl-2 (T56), Bcl-2, Bcl-xL, Mcl-1, activity of caspase-3, proliferation and induction of apoptosis in melanoma cells. Current results clearly show that the nanomolar concentration of the mTOR inhibitor everolimus in combination with the inhibitor of MAP kinase (AS-703026) or AKT kinase (MK-2206) is effective in inducing apoptosis and reducing proliferation of melanoma cells. The herein research results confirm the hypothesis on the important role of mTOR signaling in cancer progression, and gives hope that implementation of successful combination of its inhibitors will find recognition and application in cancer treatment in the near future.
黑色素瘤是最具侵袭性、对治疗耐药的皮肤癌。雷帕霉素的哺乳动物靶点（mTOR）是一种整合细胞内和细胞外信号的丝氨酸/苏氨酸激酶，在协调细胞生长与死亡之间的平衡中起着关键作用。本研究的目的是比较mTOR抑制剂依维莫司在20 nM至10 μM浓度范围内单独使用以及与选定的下游蛋白激酶抑制剂联合使用时的影响，这些下游蛋白激酶抑制剂包括：LY294002（PI3K）、U0126（ERK1/2）、AS-703026（MEK）和MK-2206（AKT），它们对黑色素瘤细胞中促生存蛋白p-Bcl-2（S70）、p-Bcl-2（T56）、Bcl-2、Bcl-xL、Mcl-1的表达、半胱天冬酶-3的活性、增殖以及凋亡诱导的影响。目前的结果清楚地表明，纳摩尔浓度的mTOR抑制剂依维莫司与MAP激酶抑制剂（AS-703026）或AKT激酶抑制剂（MK-2206）联合使用可有效诱导黑色素瘤细胞凋亡并减少其增殖。本研究结果证实了mTOR信号传导在癌症进展中起重要作用的假设，并带来了希望，即其抑制剂的成功联合应用在不久的将来将在癌症治疗中得到认可和应用。
