Methylselenol generated from selenomethionine by methioninase downregulates integrin expression and induces caspase‐mediated apoptosis of B16F10 melanoma cells

Abstract

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.

Antitumor Activity of an Enzyme Prodrug Therapy Targeted to the Breast Tumor Vasculature

“…It also catalyzes the conversion of the prodrug selenomethionine (SeMet) to toxic methylselenol, α-ketobutyrate, and ammonia. Methylselenol has been shown to be 1000-fold more cytotoxic to various cancer cells than SeMet (9) and was found to induce apoptosis and cell cycle arrest in cancer cells (10)(11)(12). SeMet cannot be converted to methylselenol by mammalian cells and is relatively nontoxic (13,14).…”

Selenium inhibits migration of murine melanoma cells via down-modulation of IL-18 expression

“…1B and C). It has also been reported that high doses of selenium induce cell death in the B16F10 melanoma cells [20]. As shown in Fig.…”

“…Recently, many studies have reported that selenium is a strong inducer of cell death in numerous cancer cells [18]. Moreover, some studies have observed that sodium selenite exhibits anti-cancer and anti-metastatic activity against melanoma cancer cells [19][20][21].…”

Kinase Regulation by Sulfur and Selenium Containing Compounds

“…For example, in colon cancer cells (HCT116) this compound provoked gene modulation [161] related to transcription factors. In melanoma the proposed mechanism involved methylselenol, a metabolite [162] generated from SeMet by methioninase. A combined treatment with methioninase provoked phosphorylation of focal adhesion kinase (FAK) and Akt and activation of p38, PKC-delta and NF-kappaB.…”