LKB1 attenuates the transport activity of GLUT1 by regulating the alternative splicing of PKM1/PKM2 in cervical cancer.

objectiveLiver kinase B1 (LKB1) is a tumor suppressor that negatively regulates glucose transporter 1 (GLUT1) in Peutz-Jeghers Syndrome, but its mechanism in cervical cancer is unclear.

methodsLKB1 expression was detected in cervical cancer specimens by real-time polymerase chain reaction. The double directional genetic manipulation, Nuclear and Cytoplasmic Protein separation technique and immunofluorescence were performed to detect the regulatory relationships among LKB1, pyruvate kinase isozyme type M2 (PKM2), hypoxia-inducible factor 1α (HIF-1α), and GLUT1 in cervical cancer cells, and Plasma Membrane and Cytoplasmic Protein separation technique and glucose uptake assay were used to verify the transport activity of GLUT1. LKB1-overexpression and -knockdown cervical cancer cell lines were generated in vitro.

resultsLKB1 messenger RNA level was lower in cervical cancer tissues than in matched paracancerous tissues. LKB1 was highly expressed in the cytoplasm of C33A, but was absent in its nucleus. And LKB1 was absent in SiHa. LKB1 regulated the alternative splicing of PKM1/PKM2. LKB1 overexpression significantly downregulated the PKM2pS37 expression in the nucleus and cytoplasm, the HIF-1α expression in the nucleus, and the GLUT1 expression in the plasma membrane. PKM2 knockdown reduced the nuclear accumulation of HIF-1α. Moreover, PKM2/HIF-1α knockdown reduced the glucose uptake of GLUT1. LKB1 negatively regulated the interaction between PKM2 and HIF-1α via AMPK signaling so as to inhibit the malignant phenotype of cervical cancer cells.

conclusionLKB1 attenuates GLUT1 transport activity by inhibiting the PKM2/HIF-1α pathway, supporting the important roles of PKM2 and HIF-1α in the pathogenesis of cervical cancer.