Targeting Notch1 signaling pathway positively affects the sensitivity of osteosarcoma to cisplatin by regulating the expression and/or activity of Caspase family.

Abstract

BACKGROUND:

The introduction of cisplatin has improved the long-term survival rate in osteosarcoma patients. However, some patients are intrinsically resistant to cisplatin. This study reported that the activation of Notch1 is positively correlated with cisplatin sensitivity, evidenced by both clinical and in vitro data.

RESULTS:

In this study, a total 8 osteosarcoma specimens were enrolled and divided into two groups according to their cancer chemotherapeutic drugs sensitivity examination results. The relationship between Notch1 expression and cisplatin sensitivity of osteosarcoma patients was detected by immunohistochemistry and semi-quantitative analysis. Subsequently, two typical osteosarcoma cell lines, Saos-2 and MG63, were selected to study the changes of cisplatin sensitivity by up-regulating (NICD1 plasmid transfeciton) or decreasing (gamma-secretase complex inhibitor DAPT) the activation state of Notch1 signaling pathway. Our results showed a significant correlation between the expression of Notch1 and cisplatin sensitivity in patient specimens. In vitro, Saos-2 with higher expression of Notch1 had significantly better cisplatin sensitivity than MG63 whose Notch1 level was relatively lower. By targeting regulation in vitro, the cisplatin sensitivity of Saos-2 and MG63 had significantly increased after the activation of Notch1 signaling pathway, and vice versa. Further mechanism investigation revealed that activation/inhibition of Notch1 sensitized/desensitized cisplatin-induced apoptosis, which probably depended on the changes in the activity of Caspase family, including Caspase 3, Caspase 8 and Caspase 9 in these cells.

CONCLUSIONS:

Our data clearly demonstrated that Notch1 is critical for cisplatin sensitivity in osteosarcoma. It can be used as a molecular marker and regulator for cisplatin sensitivity in osteosarcoma patients.

• Authors: Lei Wang, Fangchun Jin, An Qin, Yongqiang Hao, Yufeng Dong, Shengfang Ge, Kerong Dai
• Journal: Molecular cancer (Mol Cancer) Vol. 13 Pg. 139 (Jun 03 2014) ISSN: 1476-4598 [Electronic] England
• PMID: 24894297 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Homeodomain Proteins
• Receptors, Notch
• Transcription Factor HES-1
• HES1 protein, human
• Caspases
• Cisplatin

Topics

• Adolescent
• Adult
• Apoptosis (drug effects)
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Caspases (metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Female
• Homeodomain Proteins (metabolism)
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Osteosarcoma (drug therapy, enzymology, pathology)
• Receptors, Notch (metabolism)
• Signal Transduction (drug effects)
• Transcription Factor HES-1
• Young Adult