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BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression.
Pan, Tianhong; Liu, Fengshuo; Hao, Xiaoxin; Wang, Shubo; Wasi, Murtaza; Song, Jian H; Lewis, Valerae O; Lin, Patrick P; Moon, Bryan; Bird, Justin E; Panaretakis, Theocharis; Lin, Sue-Hwa; Wu, Danielle; Farach-Carson, Mary C; Wang, Liyun; Zhang, Ningyan; An, Zhiqiang; Zhang, Xiang H-F; Satcher, Robert L.
Afiliación
  • Pan T; Departments of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Liu F; Departments of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • Hao X; Departments of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • Wang S; Department of Mechanical Engineering, University of Delaware, Newark, DE, USA.
  • Wasi M; Department of Mechanical Engineering, University of Delaware, Newark, DE, USA.
  • Song JH; Departments of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lewis VO; Departments of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lin PP; Departments of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Moon B; Departments of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Bird JE; Departments of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Panaretakis T; Departments of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lin SH; Departments of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Departments of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wu D; Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, USA; Departments of Bioengineering, Rice University, Houston, TX, USA.
  • Farach-Carson MC; Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX, USA; Departments of BioSciences, Rice University, Houston, TX, USA; Departments of Bioengineering, Rice University, Houston, TX, USA.
  • Wang L; Department of Mechanical Engineering, University of Delaware, Newark, DE, USA.
  • Zhang N; The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, USA.
  • An Z; The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, USA.
  • Zhang XH; Departments of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; Departments of Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA; Departments of Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Departments of McNai
  • Satcher RL; Departments of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: rlsatcher@mdanderson.org.
Cancer Lett ; 596: 217009, 2024 Aug 01.
Article en En | MEDLINE | ID: mdl-38849015
ABSTRACT
Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteocitos / Neoplasias Óseas / Carcinoma de Células Renales / Proteínas de la Matriz Extracelular / Apoptosis / Uniones Comunicantes / Neoplasias Renales Límite: Animals / Female / Humans Idioma: En Revista: Cancer Lett Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Irlanda
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteocitos / Neoplasias Óseas / Carcinoma de Células Renales / Proteínas de la Matriz Extracelular / Apoptosis / Uniones Comunicantes / Neoplasias Renales Límite: Animals / Female / Humans Idioma: En Revista: Cancer Lett Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Irlanda