Methylselenol generated from selenomethionine by methioninase downregulates integrin expression and induces caspase-mediated apoptosis of B16F10 melanoma cells.
Melanoma is a highly metastatic cancer resistant to current chemotherapeutic and radiotherapeutic approaches. Several studies have shown that interactions between cancer cells and the extracellular matrix (ECM) are critical for the survival and invasion of metastatic cancer cells. In this study, we examine the effects of methylselenol generated from selenomethionine (SeMet) by methioninase (METase) on cell proliferation, adhesion, and expression of integrins in murine melanoma B16F10 cells, which are metastatic in the lungs of syngeneic C57BL/6J mice. Combined treatment with SeMet-METase decreased the expression of integrins alpha(4), beta(1), alpha(nu), and beta(3), and inhibited melanoma-ECM adhesion. Caspase-mediated apoptosis was induced following loss of cell adherence. Phosphorylation of focal adhesion kinase (FAK) and Akt, related to integrin-mediated survival, were decreased upon treatment with SeMet-METase while phosphorylation of p38, PKC-delta, and IkappaBalpha increased. In the presence of specific inhibitors of p38, PKC-delta, and NF-kappaB, expression of integrins and cell adhesion to ECM were maintained and cell apoptosis was prevented in SeMet-METase-treated melanoma cells. Treatment with caspase inhibitors restored cell viability and blocked poly (ADP-ribose) polymerase (PARP) cleavage, but did not restore integrin expression and cell adhesion to ECMs reduced by SeMet-METase. Based on these results, we propose that combined treatment with SeMet-METase induces caspase-mediated apoptosis in melanoma cells by altering integrin expression and adhesion. Furthermore, activation of p38, PKC-delta, and NF-kappaB is a prerequisite for the down-regulation of integrin expression, followed by detachment-mediated apoptosis.
Kim
Aeyung
A
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Oh
Jang-Hee
JH
Park
Jong-Min
JM
Chung
An-Sik
AS
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D013437:Carbon-Sulfur Lyases / Q000378:metabolism* / Q000494:pharmacology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002448:Cell Adhesion; D002453:Cell Cycle; D049109:Cell Proliferation; D048430:Cell Shape; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000432:Methanol / Q000031:analogs & derivatives; D051379:Mice; D009942:Organometallic Compounds / Q000378:metabolism*; D016566:Organoselenium Compounds; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012645:Selenomethionine / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018038:Sodium Selenite / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D016023:Integrins; D009942:Organometallic Compounds; D016566:Organoselenium Compounds; C019003:methaneselenol; D012645:Selenomethionine; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase; D018038:Sodium Selenite; D000432:Methanol