Abstract
Lkb1 is a central regulator of cell polarity and energy metabolism through its capacity to activate the AMP-activated protein kinase (AMPK)-related family of protein kinases. Germ line-inactivating mutation of Lkb1 leads to Peutz-Jeghers syndrome, which is characterized by benign hamartomas and a susceptibility to malignant epithelial tumors. Mutations in Lkb1 are also found in sporadic carcinomas, most frequently in lung cancers associated with tobacco carcinogen exposure. The basis for Lkb1-dependent tumor suppression is not defined. Here, we uncover a marked sensitivity of Lkb1 mutant mice to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Lkb1(+/-) mice are highly prone to DMBA-induced squamous cell carcinoma (SCC) of the skin and lung. Confirming a cell autonomous tumor suppressor role of Lkb1, mice with epidermal-specific Lkb1 deletion are also susceptible to DMBA-induced SCC and develop spontaneous SCC with long latency. Restoration of wild-type Lkb1 causes senescence in tumor-derived cell lines, a process that can be partially bypassed by inactivation of the Rb pathway, but not by inactivation of p53 or AMPK. Our data indicate that Lkb1 is a potent suppressor of carcinogen-induced skin and lung cancers and that downstream targets beyond the AMPK-mTOR pathway are likely mediators of Lkb1-dependent tumor suppression.
Highlights
The Lkb1 tumor suppressor encodes a serine-threonine kinase that is mutated in individuals with the Peutz-Jeghers polyposis and cancer syndrome (PJS) [1, 2]
The increased mortality in the Lkb1+/cohort was due to the development of invasive skin and lung cancers, tumors types that were not observed in wild type animals (Fig. 1B, 1Ci, and Table in 1D)
We describe the development of genetic models that demonstrate an important role of Lkb1 in suppression of carcinogen-induced tumorigenesis
Summary
The Lkb tumor suppressor encodes a serine-threonine kinase that is mutated in individuals with the Peutz-Jeghers polyposis and cancer syndrome (PJS) [1, 2]. Carcinomas in PJS patients arise independently of the hamartomas, the mechanisms by which Lkb controls benign polyposis and malignancy may be distinct [5]. Lkb is mutated in sporadic cancers whose spectrum of tumor types suggests cooperation with exposure to environmental carcinogens. Lkb mutations in lung cancer are highly correlated with a history of tobacco smoking and show a preferential occurrence of GC:TA substitutions, suggesting a mutational effect of polycyclic aromatic hydrocarbon adducts from tobacco carcinogens [8]. Other carcinomas exhibiting Lkb mutations include head and neck squamous cell carcinoma and pancreatic cancer [9], which are associated with tobacco smoking
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