Downregulation of FAPP2 gene induces cell autophagy and inhibits PI3K/AKT/mTOR pathway in T-cell acute lymphoblastic leukemia.
Tian YuanJinhuan WangCe ShiYi WangBing XiaWen XuHongliang YangYaling YangMatthew T YeSamah KhalidYong LiangChen TianM James YouYafei WangPublished in: Hematological oncology (2021)
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.
Keyphrases
- induced apoptosis
- cell proliferation
- signaling pathway
- endoplasmic reticulum stress
- cell cycle arrest
- acute lymphoblastic leukemia
- cell death
- high dose
- oxidative stress
- low dose
- stem cells
- squamous cell carcinoma
- pi k akt
- copy number
- drug delivery
- radiation therapy
- cell cycle
- transcription factor
- allogeneic hematopoietic stem cell transplantation
- rectal cancer
- bone marrow
- single molecule
- mass spectrometry
- mesenchymal stem cells
- genome wide identification