title: L-cysteine as a regulator for arsenic-mediated cancer-promoting and anti-cancer effects.
abstract: Previous studies have shown that activities of tyrosine kinases and secretion of the active form of matrix metalloproteinase-2 (MMP-2) are correlated with promotion of tumor growth, while apoptotic cell death in cancer cells is correlated with anti-cancer effects. Although arsenic has been reported to have both cancer-promoting and anti-cancer effects, the mechanisms of the arsenic-mediated bidirectional effects remain unknown. We examined the effects of arsenic on both proto-oncogene c-RET-transfected NIH3T3 cells with benign characters and oncogenic RET-MEN2A-transfected NIH3T3 cells with malignant characters. Arsenic promoted not only c-RET tyrosine kinase activity but also genetically activated RET-MEN2A kinase activity with promotion of dimer formation of RET proteins. Arsenic also increased secretion of the active form of MMP-2 in both RET-MEN2A-transfectants and c-RET-transfectants. On the other hand, arsenic promoted poly-(ADP-ribose) polymerase (PARP) degradation and cell death in both malignant and non-malignant cells. Interestingly, l-cysteine inhibited the arsenic-mediated tumor-promoting effects (activation of kinases and MMP-2 secretion) but not arsenic-mediated anti-cancer effects (PARP degradation and cell death). Our results suggest redox-linked regulation of arsenic-mediated activities of kinases and MMP-2 secretion but not arsenic-mediated cell death. Our results also suggest that l-cysteine is an ideal supplement that inhibits arsenic-mediated tumor-promoting effects without affecting arsenic-mediated anti-cancer effects.
authors.affiliation: Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai-shi, Aichi 487-8501, Japan. katomasa@isc.chubu.ac.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.forename: Mayuko Y
authors.initials: MY
authors.lastname: Kumasaka
authors.forename: Kozue
authors.initials: K
authors.lastname: Takeda
authors.forename: Khaled
authors.initials: K
authors.lastname: Hossain
authors.forename: Machiko
authors.initials: M
authors.lastname: Iida
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yajima
authors.forename: Yuji
authors.initials: Y
authors.lastname: Goto
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Ohgami
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000633:toxicity*; D018053:Arsenites / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000633:toxicity*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D041681:NIH 3T3 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity*; D014162:Transfection
chemical_list: D016588:Anticarcinogenic Agents; D018053:Arsenites; D002274:Carcinogens, Environmental; D004791:Enzyme Inhibitors; D017670:Sodium Compounds; C017947:sodium arsenite; D011065:Poly(ADP-ribose) Polymerases; D020778:Matrix Metalloproteinase 2; D003545:Cysteine