A leucine-rich diet modulates the tumor-induced down-regulation of the MAPK/ERK and PI3K/Akt/mTOR signaling pathways and maintains the expression of the ubiquitin-proteasome pathway in the placental tissue of NMRI mice.
Placental tissue injury is concomitant with tumor development. We investigated tumor-driven placental damage by tracing certain steps of the protein synthesis and degradation pathways under leucine-rich diet supplementation in MAC16 tumor-bearing mice. Cell signaling and ubiquitin-proteasome pathways were assessed in the placental tissues of pregnant mice, which were distributed into three groups on a control diet (pregnant control, tumor-bearing pregnant, and pregnant injected with MAC-ascitic fluid) and three other groups on a leucine-rich diet (pregnant, tumor-bearing pregnant, and pregnant injected with MAC-ascitic fluid). MAC tumor growth down-regulated the cell-signaling pathways of the placental tissue and decreased the levels of IRS-1, Akt/PKB, Erk/MAPK, mTOR, p70S6K, STAT3, and STAT6 phosphorylated proteins, as assessed by the multiplex Millipore Luminex assay. Leucine supplementation maintained the levels of these proteins within the established cell-signaling pathways. In the tumor-bearing group (MAC) only, the placental tissue showed increased PC5 mRNA expression, as assessed by quantitative RT-PCR, decreased 19S and 20S protein expression, as assessed by Western blot analysis, and decreased placental tyrosine levels, likely reflecting up-regulation of the ubiquitin-proteasome pathway. Similar effects were found in the pregnant injected with MAC-ascitic fluid group, confirming that the effects of the tumor were mimicked by MAC-ascitic fluid injection. Although tumor progression occurred, the degradation pathway-related protein levels were modulated under leucine-supplementation conditions. In conclusion, tumor evolution reduced the protein expression of the cell-signaling pathway associated with elevated protein degradation, thereby jeopardizing placental activity. Under the leucine-rich diet, the impact of cancer on placental function could be minimized by improving the cell-signaling activity and reducing the proteolytic process.
Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil.
Laís Rosa
LR
Viana
Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, Sao Paulo, Brazil cintgoma@unicamp.br.
Maria Cristina Cintra
MC
Gomes-Marcondes
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D019587:Dietary Supplements; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007930:Leucine / Q000008:administration & dosage*; D051379:Mice; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D007930:Leucine; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
MAC16; fetal; leucine; placenta; tumor