Therapeutic implications of targeting the PI3Kinase/AKT/mTOR signaling module in melanoma therapy.
Therapeutic implications of targeting the PI3Kinase/AKT/mTOR signaling module in melanoma therapy.
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DOI：
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发表时间：
2012
影响因子：
5.3
通讯作者：
Ali R. Jazirehi;P. Wenn;Mohsen Damavand
中科院分区：
文献类型：
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作者：
Ali R. Jazirehi;P. Wenn;Mohsen Damavand
PI 3激酶/AKT/mTOR信号传导模块涉及各种细胞功能，包括细胞存活、生长和增殖、葡萄糖代谢、凋亡、迁移和血管生成。AKT及其上游和下游调节因子的表达增加与几种类型的癌症有关。在近60%的黑色素瘤中观察到AKT的异常表达，通过凋亡分子Bad和Cas-pase-9的失活而达到凋亡抗性的顶峰。AKT通过与NF-κB、ERK 1/2、JNK和p38 MAPK信号通路的相互作用，诱导过多的细胞效应，通常导致肿瘤的发生和进展。由于经常观察到对其他常见癌症治疗（如化学疗法、免疫疗法和放射）的抗性，以及PI 3激酶/AKT/mTOR信号传导模块的组成性活化的有害后果，靶向抑制该模块中涉及的效应物和底物已成为黑色素瘤分子靶向治疗的可行且有吸引力的选择。在I期和II期临床试验中，该模块的各种组分的药理学抑制剂，无论是单独使用还是与其他药剂组合使用，都显示出各种肿瘤的增殖、肿瘤发生、细胞生长和存活的显著降低。一些抑制剂甚至获得了食品和药物管理局（FDA）的批准。这篇综述总结了目前的知识，这个模块，它的串扰与其他主要的细胞存活途径和它的靶向抑制黑色素瘤的治疗目的。
The PI3Kinase/AKT/mTOR signaling module is implicated in various cellular functions including cell survival, growth and proliferation, glucose metabolism, apoptosis, migration, and angiogenesis. Increased expression of AKT and its up- and downstream regulators is linked to several types of cancer. Aberrant expression of AKT is observed in nearly 60% of melanomas culminating in apoptosis resistance via deactivation of apoptotic molecules Bad and Cas-pase-9. Through cross-talk with NF-κB, ERK1/2, JNK and p38MAPK signaling pathways, AKT induces a plethora of cellular effects often leading to tumor development and progression. Due to frequently observed resistance to other common cancer treatments such as chemotherapy, immunotherapy, and radiation, and the detrimental consequences of constitutive activation of the PI3Kinase/AKT/mTOR signaling module, targeted inhibition of the effectors and substrates involved in this module has become a viable and attractive option for molecular targeted therapy in melanoma. Pharmacological inhibitors of various components of this module, either alone or in combination with other agents, have shown significant decrease in proliferation, tumorigenesis, cell growth and survival of various tumors in phases I and II clinical trials. Some inhibitors have even received their Food and Drug Administration (FDA) approval. This review summarizes the current knowledge on this module, its cross-talk with other major cell survival pathways and its targeted inhibition for therapeutic purposes in melanoma.