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Decreased lactate dehydrogenase B expression enhances claudin 1-mediated hepatoma cell invasiveness via mitochondrial defects

Kim, JH; Kim, EL; Lee, YK; Park, CB; Kim, BW; Wang, HJ; Yoon, CH; Lee, SJ; Yoon, G
Experimental cell research, 317(8):1108-1118, 2011
Journal Title
Experimental cell research
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.
MeSH terms
Carcinoma, Hepatocellular/*pathologyCell Line, TumorCell Respiration/physiologyGlycolysis/physiologyHumansIsoenzymes/genetics/metabolismL-Lactate Dehydrogenase/genetics/*metabolismLactic Acid/metabolismLiver Neoplasms/*pathologyMembrane Proteins/*metabolismMitochondria/*microbiology/*pathology*Neoplasm InvasivenessRNA, Small Interfering/genetics/metabolism
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
Journal Papers > School of Medicine / Graduate School of Medicine > Surgery
AJOU Authors
박, 찬배김, 봉완왕, 희정윤, 계순
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