Leptin's mitogenic effect in human liver cancer cells requires induction of both methionine adenosyltransferase 2A and 2beta.
Leptin is an adiopokine that plays a pivotal role in the progression of liver fibrogenesis and carcinogenesis. Recently, leptin was shown to be mitogenic in human liver cancer cell lines HepG2 and Huh7. Whether leptin can act as a mitogen in normal hepatocytes is unclear. Methionine adenosyltransferase (MAT) is an essential enzyme that catalyzes the formation of S-adenosylmethionine (SAMe), the principal methyl donor and precursor of polyamines. Two genes (MAT1A and MAT2A) encode for the catalytic subunit of MAT, whereas a third gene (MAT2beta) encodes for a regulatory subunit that modulates the activity of MAT2A-encoded isoenzyme. The aims of this study were to examine whether leptin's mitogenic activity involves MAT2A and MAT2beta and whether this can be modulated. We found that leptin is mitogenic in HepG2 cells but not in primary human or mouse hepatocytes. Leptin induced the expression of MAT2A and MAT2beta in HepG2 cells and normal human and mouse hepatocytes, but although it increased SAMe level in HepG2 cells, it had no effect on SAMe level in normal hepatocytes. Leptin-mediated induction of MAT genes and growth in HepG2 cells required activation of extracellular signal-regulated kinase and phosphatidylinositol-3-kinase signaling pathways. Treatment with SAMe or its metabolite methylthioadenosine (MTA) lowered expression of MAT2A and MAT2beta and blocked leptin-induced signaling, including an increase in MAT gene expression and growth. Increased expression of MAT2A and MAT2beta is required for leptin to be mitogenic, although by entirely different mechanisms.


CONCLUSIONS
Leptin induces MAT2A and MAT2beta expression in HepG2 cells and normal hepatocytes but is mitogenic only in HepG2 cells. Pharmacological doses of SAMe or MTA lower expression of both MAT2A and MAT2beta and interfere with leptin signaling.
Ramani
Komal
K
Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, University of Southern California, Los Angeles, CA 90033, USA.
Yang
Heping
H
Xia
Meng
M
Ara
Ainhoa Iglesias
AI
Mato
José M
JM
Lu
Shelly C
SC
D000818:Animals; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology; D006801:Humans; D020738:Leptin / Q000502:physiology*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D008297:Male; D008716:Methionine Adenosyltransferase / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics
D020738:Leptin; D012334:RNA, Neoplasm; D012313:RNA; C527161:MAT2A protein, human; C527162:MAT2B protein, human; D008716:Methionine Adenosyltransferase