TY - JOUR
T1 - Theophylline induces differentiation and modulates cytoskeleton dynamics and cytokines secretion in human melanoma-initiating cells
AU - Cordella, Martina
AU - Tabolacci, Claudio
AU - Senatore, Cinzia
AU - Rossi, Stefania
AU - Mueller, Sabina
AU - Lintas, Carla
AU - Eramo, Adriana
AU - D'Arcangelo, Daniela
AU - Valitutti, Salvatore
AU - Facchiano, Antonio
AU - Facchiano, Francesco
PY - 2019/8/1
Y1 - 2019/8/1
N2 - Aims: Cutaneous melanoma is the most aggressive skin cancer, derived from neoplastic transformation of melanocytes. Since several evidences highlighted the importance of a hierarchical model of differentiation among cancer cells, closely related to resistance mechanisms and tumor relapse, we investigated the effects of theophylline (Theo), a methylxanthine commonly used in treatment of respiratory diseases, on melanoma cells with different degree of differentiation, including patient-derived melanoma-initiating cells. Materials and methods: The antiproliferative and antimetastatic effects of Theo was demonstrated by cell counting, adhesion and migration assays on A375 and SK-MEL-30 cells. Further, Theo ability to reduce cell growth was highly significant in A375-derived spheroids and in two patient-derived melanoma-initiating cells (MICs). In order to identify pathways potentially involved in the antineoplastic properties of Theo, a comparative mass spectrometry proteomic analysis was used. Then, melanin content, tyrosinase and tissue transglutaminase activities as differentiation markers and actin re-organization through confocal microscopy were evaluated. Furthermore, a secretome profile of MICs after Theo treatments was performed by multiplex immunoassay. Key findings: Obtained results demonstrate inhibitory effects of Theo on melanoma cell proliferation and migration, mainly in MICs, together with the induction of differentiation parameters. Moreover, our data indicate that the known anti-melanoma effect of Theo is due also to its ability to interfere with cytoskeleton dynamics and to induce the secretion of inflammatory molecules involved in recruitment of immunosuppressive cells in tumor microenvironment. Significance: Data strongly suggest that Theo supplement, either as drug or as dietary supply, may represent a potent additional weapon against melanoma.
AB - Aims: Cutaneous melanoma is the most aggressive skin cancer, derived from neoplastic transformation of melanocytes. Since several evidences highlighted the importance of a hierarchical model of differentiation among cancer cells, closely related to resistance mechanisms and tumor relapse, we investigated the effects of theophylline (Theo), a methylxanthine commonly used in treatment of respiratory diseases, on melanoma cells with different degree of differentiation, including patient-derived melanoma-initiating cells. Materials and methods: The antiproliferative and antimetastatic effects of Theo was demonstrated by cell counting, adhesion and migration assays on A375 and SK-MEL-30 cells. Further, Theo ability to reduce cell growth was highly significant in A375-derived spheroids and in two patient-derived melanoma-initiating cells (MICs). In order to identify pathways potentially involved in the antineoplastic properties of Theo, a comparative mass spectrometry proteomic analysis was used. Then, melanin content, tyrosinase and tissue transglutaminase activities as differentiation markers and actin re-organization through confocal microscopy were evaluated. Furthermore, a secretome profile of MICs after Theo treatments was performed by multiplex immunoassay. Key findings: Obtained results demonstrate inhibitory effects of Theo on melanoma cell proliferation and migration, mainly in MICs, together with the induction of differentiation parameters. Moreover, our data indicate that the known anti-melanoma effect of Theo is due also to its ability to interfere with cytoskeleton dynamics and to induce the secretion of inflammatory molecules involved in recruitment of immunosuppressive cells in tumor microenvironment. Significance: Data strongly suggest that Theo supplement, either as drug or as dietary supply, may represent a potent additional weapon against melanoma.
U2 - 10.1016/j.lfs.2019.05.050
DO - 10.1016/j.lfs.2019.05.050
M3 - Articolo
VL - 230
SP - 121
EP - 131
JO - Life Sciences
JF - Life Sciences
SN - 0024-3205
ER -