TY - JOUR
T1 - Downregulation of FAPP2 gene induces cell autophagy and inhibits PI3K/AKT/mTOR pathway in T-cell acute lymphoblastic leukemia
AU - Yuan, Tian
AU - Wang, Jinhuan
AU - Shi, Ce
AU - Wang, Yi
AU - Xia, Bing
AU - Xu, Wen
AU - Yang, Hongliang
AU - Yang, Yaling
AU - Ye, Matthew T.
AU - Khalid, Samah
AU - Liang, Yong
AU - Tian, Chen
AU - You, M. James
AU - Wang, Yafei
N1 - Funding Information:
This study was supported by Natural Science Foundation of Tianjin (18JCYBJC91800), National Natural Science Foundation Young Scientist fund (81800148), and National Natural Science Foundation (81670104).
Publisher Copyright:
© 2021 John Wiley & Sons Ltd.
PY - 2022/4
Y1 - 2022/4
N2 - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Most patients with T-ALL are treated with high-dose multi-agent chemotherapy due to limited targeted therapeutic options. To further investigate its pathogenesis and establish new therapeutic targets, we studied the role of FAPP2, a Golgi protein, that is, highly expressed in T-ALL, in the growth and function of T-ALL. We found that T-ALL cells underwent reduced cell proliferation and sub-G1 accumulation after knocking down of FAPP2 gene using shRNA systems. Instead, FAPP2 downregulation promoted cell autophagy. The level of autophagy markers, LC3Ⅱ/Ⅰ, Beclin1, and ATG5, was markedly increased, whereas that of P62 decreased after FAPP2 knocking down in T-ALL cells. FAPP2 knocking down led to the accumulation of LC3 in the cytoplasm of T-ALL cells as shown by fluorescence microscopy. In addition, the level of PI(4)P and PI(3,4,5)P decreased and phosphorylation of P-AKT and P-mTOR were downregulated in FAPP2 knock-down cells. In summary, our results show that decreased expression of FAPP2 inhibited cell proliferation, resulted in the sub-G1 phase accumulation of T-ALL cells, and enhanced autophagy of T-ALL cells, likely mediated by PI(4)P, PI(3,4,5)P, and PI3K/AKT/mTOR pathway. Our results provide a new insight into the pathogenesis and development of potential targeted therapy of T-ALL.
AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Most patients with T-ALL are treated with high-dose multi-agent chemotherapy due to limited targeted therapeutic options. To further investigate its pathogenesis and establish new therapeutic targets, we studied the role of FAPP2, a Golgi protein, that is, highly expressed in T-ALL, in the growth and function of T-ALL. We found that T-ALL cells underwent reduced cell proliferation and sub-G1 accumulation after knocking down of FAPP2 gene using shRNA systems. Instead, FAPP2 downregulation promoted cell autophagy. The level of autophagy markers, LC3Ⅱ/Ⅰ, Beclin1, and ATG5, was markedly increased, whereas that of P62 decreased after FAPP2 knocking down in T-ALL cells. FAPP2 knocking down led to the accumulation of LC3 in the cytoplasm of T-ALL cells as shown by fluorescence microscopy. In addition, the level of PI(4)P and PI(3,4,5)P decreased and phosphorylation of P-AKT and P-mTOR were downregulated in FAPP2 knock-down cells. In summary, our results show that decreased expression of FAPP2 inhibited cell proliferation, resulted in the sub-G1 phase accumulation of T-ALL cells, and enhanced autophagy of T-ALL cells, likely mediated by PI(4)P, PI(3,4,5)P, and PI3K/AKT/mTOR pathway. Our results provide a new insight into the pathogenesis and development of potential targeted therapy of T-ALL.
KW - FAPP2
KW - PI3K/AKT/mTOR
KW - T-cell acute lymphoblastic leukemia
KW - autophagy
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U2 - 10.1002/hon.2948
DO - 10.1002/hon.2948
M3 - Article
C2 - 34796518
AN - SCOPUS:85119586324
SN - 0278-0232
VL - 40
SP - 249
EP - 257
JO - Hematological Oncology
JF - Hematological Oncology
IS - 2
ER -