Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment
Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment
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DOI：
10.1111/j.1365-2133.2007.07821.x
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发表时间：
2007-06-01
影响因子：
10.3
通讯作者：
Schittek, B.
中科院分区：
文献类型：
--
作者：
Meier, F.;Busch, S.;Schittek, B.
背景在黑色素瘤中，几种信号通路被组成性激活。其中，RAS/RAF/MEK/ERK（MAPK）和PI 3 K/AKT（AKT）信号通路通过多种机制被激活，在黑色素瘤的发生和发展中发挥重要作用。目的在本研究中，我们研究了靶向MAPK和/或AKT信号通路是否对黑色素瘤有治疗作用。（BAY 43-9006，PD 98059，U 0126，wortmannin，LY 294002）在不同水平上抑制MAPK和AKT信号通路，并在单层和器官型皮肤培养中评价对黑色素瘤细胞生长、存活和侵袭的影响。相比之下，MAPK和AKT信号通路的组合靶向在单层培养中显著抑制生长并增强凋亡。为了在更生理的背景下验证我们的数据，我们将黑色素瘤细胞掺入再生的人类皮肤中，模仿人类黑色素瘤的微环境。MAPK和AKT抑制剂的组合完全抑制黑色素瘤细胞的侵袭性肿瘤生长在再生human skin.Conclusions结合靶向的MAPK和AKT信号通路是一个很有前途的黑色素瘤治疗策略，应鼓励进一步深入调查。
Background In melanoma, several signalling pathways are constitutively activated. Among them, the RAS/RAF/MEK/ERK (MAPK) and PI3K/AKT (AKT) signalling pathways are activated through multiple mechanisms and appear to play a major role in melanoma development and progression.Objectives In this study, we examined whether targeting the MAPK and/or AKT signalling pathways would have therapeutic effects against melanoma.Methods Using a panel of pharmacological inhibitors (BAY 43-9006, PD98059, U0126, wortmannin, LY294002) we inhibited the MAPK and AKT signalling pathways at different levels and evaluated the effects on growth, survival and invasion of melanoma cells in monolayer and organotypic skin culture.Results Antiproliferative and proapoptotic effects of inhibitors alone in monolayer culture were disappointing and varied among the different cell lines. In contrast, combined targeting of the MAPK and AKT signalling pathways significantly inhibited growth and enhanced apoptosis in monolayer culture. To verify our data in a more physiological context we incorporated melanoma cells into regenerated human skin mimicking the microenvironment of human melanoma. Combinations of MAPK and AKT inhibitors completely suppressed invasive tumour growth of melanoma cells in regenerated human skin.Conclusions Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations.