GAS2-Calpain2 axis contributes to the growth of leukemic cells

• Published in: Acta biochimica et biophysica Sinica 2015-10, Vol.47 (10), p.795-804
• Main Authors: Sun, Lili, Zhou, Haixia, Liu, Hong, Ge, Yue, Zhang, Xiuyan, Ma, Wenjuan, Wu, Depei, Zhao, Yun
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor - metabolism; Calpain - metabolism; Cell Line, Tumor; Cell Proliferation; Humans; Jurkat Cells; Jurkat细胞; Leukemia - metabolism; Leukemia - pathology; Microfilament Proteins - metabolism; Signal Transduction; 急性白血病; 淋巴白血病; 白血病细胞; 细胞周期; 细胞生长; 蛋白酶活性; 轴
• ISSN: 1672-9145; 1745-7270
• DOI: 10.1093/abbs/gmv080

Growth arrest specific 2 （GAS2） modulates cell cycle, apoptosis, and Calpain activity. GAS2-Calpain2 axis is required for the growth of BCR-ABL＋ hematopoietic cells and chronic myeloid leukemia cells. However, the expression of GAS2 in acute leukemia patients remains unclear and what role GAS2- Calpain2 axis plays in these leukemic cells is not known yet. In this study, GAS2 was found to have significantly higher expression in 16 various leukemic cell lines than in control cells. Using THP-1 cells （from acute myeloid leukemia patient, AML） and Jurkat cells （from acute lymphoid leukemia patient, ALL） as models, we found that GAS2 silence led to elevated Calpain activity, decreased cellular growth, and inhibition of colony-forming cell （CFC） production; and these effects could be rescued by GAS2 re-expression. Moreover, GAS2 s nude mice. In both THP-1 and Jurkat cells, GAS2 ence prevented tumor formation of THP-1 cells in nteracted with Calpain2 rather than Calpainl. The dominant negative form of GAS2 （GAS2DN, GAS2A171-313） had similar effects on leukemic cells through the activation of Calpain. Importantly, Calpain2 silence abolished the proliferation inhibition induced by GAS2 targeting. We also found that GAS2 was aberrantly expressed and Calpain activity was decreased in clinical isolates from acute leukemia patients. Taken together, our results demonstrated the deregulation of GAS2 in both AML and ALL and the requirement of GAS2-Calpain2 axis for the growth of leukemic cells, which will help to understand the molecular pathogenesis of hema- tological malignancies and possibly to develop novel approaches to treat these deadly diseases.