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: Q Zeng, J Chen, Y Li, K D Werle, R-X Zhao, C-S Quan, Y-S Wang, Y-X Zhai, J-W Wang, M Youssef, R Cui, J Liang, N Genovese, L T Chow, Y-L Li, Z-X Xu
• Journal: Oncogene (Oncogene) Vol. 36 Issue 9 Pg. 1245-1255 (03 02 2017) ISSN: 1476-5594 [Electronic] England
• PMID: 27546620 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Biomarkers, Tumor
• E6 protein, Human papillomavirus type 16
• Oncogene Proteins, Viral
• Papillomavirus E7 Proteins
• Repressor Proteins
• oncogene protein E7, Human papillomavirus type 16
• Hexokinase
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• Glucose

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Case-Control Studies
• Cell Proliferation
• Cell Transformation, Neoplastic (metabolism, pathology)
• Female
• Follow-Up Studies
• Glucose (metabolism)
• Glycolysis (physiology)
• Hexokinase (genetics, metabolism)
• Human papillomavirus 16 (physiology)
• Humans
• Mice
• Mice, Inbred C57BL
• Neoplasm Staging
• Oncogene Proteins, Viral (genetics, metabolism)
• Papillomavirus E7 Proteins (genetics, metabolism)
• Papillomavirus Infections (metabolism, pathology, virology)
• Prognosis
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Tumor Cells, Cultured
• Uterine Cervical Neoplasms (metabolism, pathology, virology)