Quantitative Proteomic Profiling Reveals That Diverse Metabolic Pathways Are Influenced by Melatonin in an in Vivo Model of Ovarian Carcinoma.
To obtain more information into the molecular mechanisms underlying ovarian cancer (OC), we proposed a comparative proteomic analysis in animals receiving long-term melatonin as therapy or only vehicle using multidimensional protein identification combined with mass spectrometry. To induce tumor, a single dose of 100 μg 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 μL of sesame oil was injected under the left ovarian bursa of 20 Fischer 344 rats. The right ovaries were injected with sesame oil only. After tumors were developed, half of the animals received intraperitoneal administration of melatonin (200 μg/100g body weight/day) for 60 days. Melatonin therapy promoted down-regulation in numerous proteins involved in OC signaling pathways. The most significant portion of these proteins are involved in several metabolic processes, mainly those associated with mitochondrial systems, generation of metabolites and energy, hypoxia-inducible factor-1 signaling, antigen processing and presentation, endoplasmic reticulum stress-associated pathways, and cancer-related proteoglycans. A small number of proteins that were overexpressed by melatonin therapy included ATP synthase subunit β, fatty acid-binding protein, and 10-kDa heat shock protein. Taken together, our findings suggest that melatonin therapy efficiently modulated important signaling pathways involved in OC, and these proteins might be further targets that should be explored in new therapeutic opportunities for OC.
Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista , Botucatu, São Paulo, Brazil.
Luiz Gustavo A
LG
Chuffa
Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista , Botucatu, São Paulo, Brazil.
Luiz Antonio
LA
Lupi Júnior
Institute of Biology, North of Parana State University - UENP , CLM, Bandeirantes, Paraná, Brazil.
Fábio R F
FR
Seiva
Department of Morphology and Pathology, UFSCar - Universidade Federal de São Carlos , São Carlos, São Paulo, Brazil.
Marcelo
M
Martinez
Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista , Botucatu, São Paulo, Brazil.
Raquel F
RF
Domeniconi
Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista , Botucatu, São Paulo, Brazil.
Patricia Fernanda F
PF
Pinheiro
Center for the Study of Venoms and Venomous Animals (CEVAP), UNESP - Univ Estadual Paulista , Botucatu, São Paulo, Brazil.
Lucilene D
LD
Dos Santos
Department of Anatomy, Institute of Biosciences, UNESP - Universidade Estadual Paulista , Botucatu, São Paulo, Brazil.
Francisco Eduardo
FE
Martinez
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects
D009363:Neoplasm Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D008550:Melatonin
ER stress; energy; mass spectrometry; melatonin; mitochondrial metabolism; ovarian cancer