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. Knock-down 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.

Genomic alterations in STK11 can predict clinical outcomes in cervical cancer patients

“…STK11/LKB1 encodes a serine/threonine kinase that activates a family of multi kinases that control cell metabolism, cell polarity, and growth. The knockdown of STK11 increased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV-transformed cells [38]. Additionally, the prognosis of patients with STK11 genomic alterations or a decreased gene expression level in several cancer types, including non-squamous cell lung cancer, breast cancer, hepatocellular carcinoma, and gastric cancer, was reportedly worse than that of those with wild-type STK11 [39,40].…”

Effects of 60�kDa prolactin and estradiol on metabolism and cell survival in cervical cancer: Co‑expression of their hormonal receptors during cancer progression

“…Zeng et al demonstrated that E6/E7 expression induces aerobic glycolysis, also known as the 'Warburg effect'. This induction is mediated by c-MYC, which elevates hexokinase-II, the rate-limiting enzyme responsible for the first step in the glycolytic pathway (60). In addition, it has been reported that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase are markedly increased in HPV-induced cervical neoplasms and mouse embryonic fibroblasts transduced with HPV 16 oncogene E6 or E6/E7 (61).…”

HPV16 E6/E7 upregulates HIF-2α and VEGF by inhibiting LKB1 in lung cancer cells

“…Recent studies had showed that high-risk HPV16 infection is closely related to the inactivation of tumor-suppressor gene LKB1 in the pathogenesis of cervical cancer, 21,22 others had found that the inactivation of tumor-suppressor gene LKB1 is also closely related to the occurrence of lung cancer; 23 however, it remains unclear whether high-risk HPV16 persistent infection is related to the inactivation of LKB1 in the occurrence of lung cancer. In this study, we have demonstrated for the first time that HPV16 is a persistent infection and the cancer proteins E6 and E7 in HPV16 have obvious inhibitory effects on LKB1.…”