Targeting LKB1 signaling in cancer
BBA - Reviews on Cancer , Volume 1835 - Issue 2 p. 194- 210
The serine/threonine kinase LKB1 is a master kinase involved in cellular responses such as energy metabolism, cell polarity and cell growth. LKB1 regulates these crucial cellular responses mainly via AMPK/mTOR signaling. Germ-line mutations in LKB1 are associated with the predisposition of the Peutz-Jeghers syndrome in which patients develop gastrointestinal hamartomas and have an enormously increased risk for developing gastrointestinal, breast and gynecological cancers. In addition, somatic inactivation of LKB1 has been associated with sporadic cancers such as lung cancer. The exact mechanisms of LKB1-mediated tumor suppression remain so far unidentified; however, the inability to activate AMPK and the resulting mTOR hyperactivation has been detected in PJS-associated lesions. Therefore, targeting LKB1 in cancer is now mainly focusing on the activation of AMPK and inactivation of mTOR. Preclinical in vitro and in vivo studies show encouraging results regarding these approaches, which have even progressed to the initiation of a few clinical trials. In this review, we describe the functions, regulation and downstream signaling of LKB1, and its role in hereditary and sporadic cancers. In addition, we provide an overview of several AMPK activators, mTOR inhibitors and additional mechanisms to target LKB1 signaling, and describe the effect of these compounds on cancer cells. Overall, we will explain the current strategies attempting to find a way of treating LKB1-associated cancer.
|LKB1, Metformin, MTOR, Peutz-Jeghers syndrome, Rapamycin, Sporadic cancer|
|BBA - Reviews on Cancer|
|Organisation||Department of Gastroenterology & Hepatology|
Korsse, S.E, Peppelenbosch, M.P, & van Veelen, W. (2013). Targeting LKB1 signaling in cancer. BBA - Reviews on Cancer (Vol. 1835, pp. 194–210). doi:10.1016/j.bbcan.2012.12.006