GAS2–Calpain2 axis contributes to the growth of leukemic cells

Abstract

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 silence prevented tumor formation of THP-1 cells in nude mice. In both THP-1 and Jurkat cells, GAS2 interacted with Calpain2 rather than Calpain1. The dominant negative form of GAS2 (GAS2DN, GAS2Δ171-313) 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 hematological malignancies and possibly to develop novel approaches to treat these deadly diseases.

<p>GAS2 Promotes Cell Proliferation and Invasion and Suppresses Apoptosis in Pediatric T-Cell Acute Lymphoblastic Leukemia and Activates Wnt/β-Catenin Pathway</p>

“…21 In addition, GAS2 is upregulated in chronic myeloid leukemia cells 12 and leukemic cells. 13 In this study, GAS2 expression was upregulated in Jurkat and CCRF-CEM cells relative to normal T lymphocytes, which is consistent with the previous studies. More and more researches have suggested that GAS2 plays a regulatory role in cell biological behaviors including cell cycle, proliferation, apoptosis and differentiation.…”

“…More and more researches have suggested that GAS2 plays a regulatory role in cell biological behaviors including cell cycle, proliferation, apoptosis and differentiation. 7,13 Huang et al 11 have indicated that GAS2 overexpression is related to cell proliferation, cell cycle and the chemotherapeutic sensitivity in colorectal cancer, and GAS2 contributes to proliferation and inhibits apoptosis of leukemic cells. 13 In this study, we demonstrated that GAS2 could promote cell proliferation and invasion, inhibit cell apoptosis and reduce the chemotherapeutic sensitivity of Jurkat and CCRF-CEM cells.…”

“…7,13 Huang et al 11 have indicated that GAS2 overexpression is related to cell proliferation, cell cycle and the chemotherapeutic sensitivity in colorectal cancer, and GAS2 contributes to proliferation and inhibits apoptosis of leukemic cells. 13 In this study, we demonstrated that GAS2 could promote cell proliferation and invasion, inhibit cell apoptosis and reduce the chemotherapeutic sensitivity of Jurkat and CCRF-CEM cells. Additionally, we further confirmed this result by detecting the expressions of two well-known proliferation markers (PCNA and ki-67 antigen) and the apoptosis-related proteins (Bcl-2 and Bax).…”

“…11 Zhou et al 12 have reported that GAS2 is upregulated in chronic myeloid leukemia cells. Sun et al 13 have indicated that GAS2 has higher expression in the leukemic cells than that in control cells and promotes the growth of leukemic cells. However, the effects of GAS2 in T-ALL and its potential molecular mechanism have not been fully elucidated.…”

Growth arrest–specific 2 protein family: Structure and function

“…36,48,51 Further, GAS2 can facilitate the tumour formation of THP-1 cells in nude mice. 51 GAS2 is reportedly involved in the disease transformation of CML 52 and exhibits an opposite effect on the inhibition or emergency granulopoiesis termination roles of ICSBP for leukaemia. 53,54 In such a scenario, GAS2, therefore, tends to be an oncogene of leukaemia, which is different from the suppressor role of GAS2 in HCC.…”