The Development of Novel Therapy Targeting Metabolic Pathway Dysregulation in Doxorubicin-resistant Bone and Soft Tissue Sarcomas

2015 Fiscal Year Final Research Report

• Project/Area Number: 26861218
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: National Cancer Center Japan
• Principal Investigator: Kobayashi Eisuke 国立研究開発法人国立がん研究センター, 中央病院, 医員 (40365292)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 肉腫 / メタボリックエラー / アルギニン / オートファジー

Outline of Final Research Achievements

We focused on the arginosuccinate synthetase 1 (ASS1), which is essential for generation of arginine with non-essential amino acids in metabolic error of cancer cell metabolism. The expression of ASS1 was reduced in Dox-resistant sarcoma cells. Interestingly, there was an inverse relationship between the expression of ASS1 and the expression of P-gp. Furthermore, the inhibition of cellular proliferation, with G1-arrest, was shown to lead to autophagy with arginine deprivation. The combination of chloroquine plus arginine deprivation was more effective than arginine deprivation alone. In ASS1 reduced cells, the expression of P-gp was upregulated in comparison to negative controls. These results indicate that the reduced expression of ASS1 expression in Dox-resistant sarcomas may contribute to drug resistance. ASS1 deficiency is a potential target for novel drug therapies.

Free Research Field

整形外科　骨軟部腫瘍