AMP-activated protein kinase and human cancer: cancer metabolism revisited
AMP-activated protein kinase and human cancer: cancer metabolism revisited
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DOI：
10.1038/ijo.2008.121
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发表时间：
2008-09-01
影响因子：
4.9
通讯作者：
Kuhajda, F. P.
中科院分区：
文献类型：
--
作者：
Kuhajda, F. P.
amp活化蛋白激酶（AMPK）及其上游激酶LKB1在能量消耗时监测和恢复细胞能量。在肝脏和骨骼肌中广泛研究发现，AMPK被磷酸化并被LKB1激活，以响应AMP/ATP比率的增加，这种情况发生在各种情况下，包括缺氧、营养饥饿和氧化还原失衡。在发现LKB1是Peutz-Jegher家族性癌症综合征中突变的肿瘤抑制基因之后，对AMPK和LKB1在癌症中的作用的兴趣已经大大增加。Peutz-Jegher综合征患者携带单个失活的LKB1基因，并且获得第二个失活病变（杂合性丧失）导致多种器官的癌症发展。因此，AMPK激活的丧失被假设促进了恶性肿瘤的发展。相反，最近在体外、人类癌症异种移植物和小鼠癌症异体移植物中，AMPK药理激活被证明对许多已建立的人类癌细胞系具有细胞毒性。以前，伴随恶性表型的细胞代谢变化在很大程度上被认为是细胞转化的结果。现在，AMPK和能量代谢与恶性表型的发展和维持有关。这些发现重新引起了人们对AMPK和癌细胞代谢作为癌症治疗潜在靶点的兴趣。
AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, act to both monitor and restore cellular energy in response to energy depletion. Studied extensively in liver and skeletal muscle, AMPK is phosphorylated and activated by LKB1 in response to increasing AMP/ATP ratios, which occur in a variety of settings including hypoxia, nutrient starvation and redox imbalance. Interest in the roles of both AMPK and LKB1 in cancer has grown substantially, following the identification of LKB1 as the tumor suppressor gene mutated in the Peutz-Jegher familial cancer syndrome. Patients with the Peutz-Jegher syndrome harbor a single inactive LKB1 gene, and acquisition of a second inactivating lesion ( loss of heterozygosity) leads to the development of the cancer in a variety of organs. Thus, the loss of AMPK activation is hypothesized to promote the development of malignancy. Conversely, pharmacological AMPK activation has recently been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft and mouse cancer allografts. Previously, changes in cell metabolism that accompanied the malignant phenotype have largely been considered a consequence of cellular transformation. Now, AMPK and energy metabolism are linked to the development and maintenance of the malignant phenotype. These findings have led to renewed interest in AMPK and cancer cell metabolism in general as potential targets for cancer therapy.