title: Decreased lactate dehydrogenase B expression enhances claudin 1-mediated hepatoma cell invasiveness via mitochondrial defects.
abstract: Aerobic lactate production of which the final step is executed by lactate dehydrogenase (LDH) is one of the typical phenotypes in invasive tumor development. However, detailed mechanism of how LDH links to cancer cell invasiveness remains unclear. This study shows that suppressed LDHB expression plays a critical role in hepatoma cell invasiveness by inducing claudin-1 (Cln-1), a tight junction protein, via mitochondrial respiratory defects. First, we found that all the SNU human hepatoma cells with increased glycolytic lactate production have the defective mitochondrial respiratory activity and the Cln-1-mediated high invasive activity. Similar results were also obtained with human hepatocellular carcinoma tissues. Unexpectedly, the increased lactate production was due to LDH isozyme shifts to LDH5 by LDHB down-expression rather than LDHA induction, implying the importance of LDHB modulation. Second, LDHB knockdown did not only trigger Cln-1 induction at the transcriptional level, but also induced respiratory impairment. Interestingly, most respiratory inhibitors except KCN induced Cln-1 expression although complex I inhibition by rotenone was most effective on Cln-1 induction. Respiratory defect-mediated Cln-1 induction was further confirmed by knockdown of NDUFA9, one of complex I subunits. Finally, ectopic expression of LDHB attenuated the invasiveness of both SNU 354 and 449 cells whereas LDHB knockdown significantly augmented the invasiveness of Chang cells with Cln-1induction. The increased invasive activity by LDHB modulation was clearly reversed by knocking-down Cln-1. Taken together, our results suggest that LDHB suppression plays an important role in triggering or maintaining the mitochondrial defects and then contributes to cancer cell invasiveness by inducing Cln-1 protein.
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Suwon 443-721, Republic of Korea.
authors.forename: June-Hyung
authors.initials: JH
authors.lastname: Kim
authors.forename: Ei-Lyoung
authors.initials: EL
authors.lastname: Kim
authors.forename: Young-Kyoung
authors.initials: YK
authors.lastname: Lee
authors.forename: Chan-Bae
authors.initials: CB
authors.lastname: Park
authors.forename: Bong-Wan
authors.initials: BW
authors.lastname: Kim
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Wang
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Gyesoon
authors.initials: G
authors.lastname: Yoon
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000502:physiology; D062445:Claudin-1; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000382:microbiology* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; C409667:lactate dehydrogenase 1