Simvastatin impairs growth hormone-activated signal transducer and activator of transcription (STAT) signaling pathway in UMR-106 osteosarcoma cells.
Recent studies have demonstrated that statins reduce cell viability and induce apoptosis in various types of cancer cells. The molecular mechanisms underlying these effects are poorly understood. The JAK/STAT pathway plays an important role in the regulation of proliferation and apoptosis in many tissues, and its deregulation is believed to be involved in tumorigenesis and cancer. The physiological activation of STAT proteins by GH is rapid but transient in nature and its inactivation is regulated mainly by the expression of SOCS proteins. UMR-106 osteosarcoma cells express a GH-responsive JAK2/STAT5 signaling pathway, providing an experimental model to study the influence of statins on this system. In this study we investigated the actions of simvastatin on cell proliferation, migration, and invasion on UMR-106 cells and examined whether alterations in GH-stimulated JAK/STAT/SOCS signaling may be observed. Results showed that treatment of osteosarcoma cells with simvastatin at 3 to 10 µM doses decreases cell proliferation, migration, and invasion in a time- and dose-dependent manner. At the molecular level, although the mechanisms used by simvastatin are not entirely clear, the effect of the statin on the reduction of JAK2 and STAT5 phosphorylation levels may partially explain the decrease in the GH-stimulated STAT5 transcriptional activity. This effect correlated with a time- and dose-dependent increase of SOCS-3 expression levels in cells treated with simvastatin, a regulatory role that has not been previously described. Furthermore, the finding that simvastatin is capable of inducing SOCS-3 and CIS genes expression shows the potential of the JAK/STAT pathway as a therapeutic target, reinforcing the efficacy of simvastatin as chemotherapeutic drug for the treatment of osteosarcoma.
Hormone Laboratory, Department of Chemistry, Universidad Nacional de Colombia, Bogotá, Colombia.
María Claudia
MC
Sandoval-Usme
Hormone Laboratory, Department of Chemistry, Universidad Nacional de Colombia, Bogotá, Colombia.
Adriana
A
Umaña-Pérez
Department of Clinical Sciences, Molecular and Translational Endocrinology Group, University of Las Palmas de Gran Canaria - Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Spain ; Associated Biomedical Unit of ULPGC-IIBM "Alberto Sols" - CSIC, Las Palmas de Gran Canaria, Spain.
Borja
B
Guerra
Octavio
O
Hernández-Perera
Laboratory of Molecular Oncology, Research Unit, Complejo Hospitalario Universitario Insular Materno Infantil, CHUIMI, Las Palmas de Gran Canaria, Spain.
Orlando
O
Hernández-Perera
Laboratory of Molecular Oncology, Research Unit, Complejo Hospitalario Universitario Insular Materno Infantil, CHUIMI, Las Palmas de Gran Canaria, Spain.
José Manuel
JM
García-Castellano
Department of Clinical Sciences, Molecular and Translational Endocrinology Group, University of Las Palmas de Gran Canaria - Cancer Research Institute of The Canary Islands (ICIC), Las Palmas de Gran Canaria, Spain ; Associated Biomedical Unit of ULPGC-IIBM "Alberto Sols" - CSIC, Las Palmas de Gran Canaria, Spain.
Leandro
L
Fernández-Pérez
Hormone Laboratory, Department of Chemistry, Universidad Nacional de Colombia, Bogotá, Colombia.
Myriam
M
Sánchez-Gómez
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D013006:Growth Hormone / Q000502:physiology*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D012516:Osteosarcoma; D051381:Rats; D011915:Rats, Inbred BUF; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D000970:Antineoplastic Agents; D013006:Growth Hormone; D053612:Janus Kinases; D050799:STAT5 Transcription Factor; D019821:Simvastatin; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C491410:Socs3 protein, rat