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The Influential Role of BCL2 Family Members in Synovial Sarcomagenesis.
Barrott, Jared J; Zhu, Ju-Fen; Smith-Fry, Kyllie; Susko, Asia M; Nollner, Dakota; Burrell, Lance D; Pozner, Amir; Capecchi, Mario R; Yap, Jeffrey T; Cannon-Albright, Lisa A; Deng, Xingming; Jones, Kevin B.
Afiliação
  • Barrott JJ; Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah.
  • Zhu JF; Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah.
  • Smith-Fry K; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
  • Susko AM; Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah.
  • Nollner D; Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah.
  • Burrell LD; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
  • Pozner A; Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah.
  • Capecchi MR; Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah.
  • Yap JT; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
  • Cannon-Albright LA; Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah.
  • Deng X; Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah.
  • Jones KB; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
Mol Cancer Res ; 15(12): 1733-1740, 2017 12.
Article em En | MEDLINE | ID: mdl-28851813
ABSTRACT
Synovial sarcomas are deadly soft tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Furthermore, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database. Conditional genetic disruption of Bcl2 in mice also led to reduced sarcomagenesis. Pharmacologic inhibition specific to BCL2 had no demonstrable efficacy against human synovial sarcoma cell lines or mouse tumors. However, targeting BCLxL in human and mouse synovial sarcoma with the small molecule BH3 domain inhibitor, BXI-72, achieved significant cytoreduction and increased apoptotic signaling. Thus, the contributory role of BCL2 in synovial sarcomagenesis does not appear to render it as a therapeutic target, but mitochondrial antiapoptotic BCL2 family members may be.Implications The association of BCL2 expression with synovial sarcoma is found to fit with a subtle, but significant, impact of its enhanced presence or absence during early tumorigenesis. However, specific pharmacologic inhibition of BCL2 does not demonstrate a persistent dependence in fully developed tumors. Conversely, inhibition of the BCL2 family member BCLxL resulted in nanomolar potency against human synovial sarcoma cell lines and 50% tumor reduction in a genetically engineered mouse model. Mol Cancer Res; 15(12); 1733-40. ©2017 AACR.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sarcoma Sinovial / Proteínas Proto-Oncogênicas c-bcl-2 / Proteína bcl-X / Carcinogênese Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sarcoma Sinovial / Proteínas Proto-Oncogênicas c-bcl-2 / Proteína bcl-X / Carcinogênese Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article