title: LKB1 inhibits HPV-associated cancer progression by targeting cellular metabolism.
abstract: Liver kinase B1 (LKB1) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus (HPV)-caused cervical cancer. However, the significance of LKB1 mutations in cervical cancer initiation and progress has not been examined. Herein, we demonstrated that, in mouse embryonic fibroblasts, loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption, lactate production and ATP generation. Knockdown of LKB1 increased and ectopic expression of LKB1 decreased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV-transformed cells. In the tumorigenesis and lung metastasis model in syngeneic mice, depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth. We showed that HPV16 E6/E7 enhanced the expression of hexokinase-ll (HK-II) in the glycolytic pathway through elevated c-MYC. Ectopic LKB1 reduced HK-II along with glycolysis. The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions. We propose that LKB1 acts as a safeguard against HPV-stimulated aerobic glycolysis and tumor progression. These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism.
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.|Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Werle
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: R-X
authors.initials: RX
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: C-S
authors.initials: CS
authors.lastname: Quan
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: Y-X
authors.initials: YX
authors.lastname: Zhai
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: J-W
authors.initials: JW
authors.lastname: Wang
authors.affiliation: Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Youssef
authors.affiliation: Department of Dermatology, Boston University, School of Medicine, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Genovese
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: L T
authors.initials: LT
authors.lastname: Chow
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Li
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, China.|Division of Hematology and Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Z-X
authors.initials: ZX
authors.lastname: Xu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009367:Neoplasm Staging; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D030361:Papillomavirus Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D006593:Hexokinase; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose