Verteporfin Inhibits the Progression of Spontaneous Osteosarcoma Caused by Trp53 and Rb1 Deficiency in Ctsk-Expressing Cells via Impeding Hippo Pathway.

Abstract

Osteosarcoma is the most common primary malignancy of bone in children and adolescents. Others and our previous studies have shown that Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) as core components of the Hippo pathway are crucial regulators of osteosarcoma formation and progression. Recent studies demonstrated that verteporfin (VP) is an inhibitor of YAP/TAZ signaling in xenograft osteosarcoma. However, whether VP can inhibit primary osteosarcoma in mice is unknown. Mutations of Trp53 and Rb1 occur in approximately 50~70% of human osteosarcoma. In this study, we successfully generated the Ctsk-Cre;Trp53f/f/Rb1f/f mice in which Trp53/Rb1 was ablated in Ctsk-expressing cells and found that Ctsk-Cre;Trp53f/f/Rb1f/f mice spontaneously developed osteosarcoma with increased expansive osteoid lesions in the cortical bone with aging. Loss of Trp53/Rb1 in Ctsk-expressing cells significantly promoted the expression and nuclear translocation of YAP/TAZ. Micro-CT results showed that inhibition of YAP/TAZ by VP delays osteosarcoma progression and protected against bone erosion in Ctsk-Cre;Trp53f/f/Rb1f/f mice. Importantly, the Kaplan-Meier survival curves displayed a significantly longer survival rate after VP treatment in Ctsk-Cre;Trp53f/f/Rb1f/f mice compared to non-injected groups. In vitro studies further showed that VP inhibited the proliferation, migration and invasion in Trp53/Rb1-mutant Ctsk-expressing cells. Moreover, the results from promoter luciferase activity analysis showed that the transcriptional activity of YAP/TAZ was significantly increased in osteosarcoma tissue from Ctsk-Cre;Trp53f/f/Rb1f/f mice, which was attenuated by VP treatment. Overall, these findings suggest that targeting Hippo pathway by VP may be a potential therapeutic strategy for osteosarcoma.

• Authors: Yang Li, Shuting Yang, Shuying Yang
• Journal: Cells (Cells) Vol. 11 Issue 8 (04 16 2022) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 35456040 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• RB1 protein, human
• Retinoblastoma Binding Proteins
• Transcription Factors
• Verteporfin
• Ubiquitin-Protein Ligases
• CTSK protein, human
• Cathepsin K
• Ctsk protein, mouse

Topics

• Adolescent
• Animals
• Bone Neoplasms (drug therapy, genetics, metabolism)
• Cathepsin K (metabolism)
• Hippo Signaling Pathway
• Humans
• Mice
• Osteosarcoma (drug therapy, metabolism)
• Retinoblastoma Binding Proteins
• Transcription Factors (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Verteporfin (pharmacology, therapeutic use)