LKB1 Deficiency Sensitizes Mice to Carcinogen-Induced Tumorigenesis

• Published in: Cancer research (Chicago, Ill.) Vol. 68; no. 1; pp. 55 - 63
• Main Authors: GURUMURTHY, Sushma, HEZEL, Aram F, BERGER, Justin H, BOSENBERG, Marcus W, BARDEESY, Nabeel
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 2008
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - toxicity; Animals; Antineoplastic agents; Biological and medical sciences; Carcinogens - toxicity; Cell Transformation, Neoplastic - chemically induced; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Epidermis - drug effects; Epidermis - pathology; Lung Neoplasms - chemically induced; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical sciences; Mice; Mice, Mutant Strains; Neoplasms, Squamous Cell - chemically induced; Neoplasms, Squamous Cell - genetics; Neoplasms, Squamous Cell - pathology; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Retinoblastoma Protein - antagonists & inhibitors; Retinoblastoma Protein - metabolism; Signal Transduction; Skin Neoplasms - chemically induced; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism; Tumors; Carcinogen; Vertebrata; Mammalia; Mouse; Toxicity; STK11 gene; Animal; Deficiency; Rodentia; Tumorigenicity; Carcinogenesis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-3225

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.