-
Li Zhang,
Ruijing Xiao,
Jie Xiong,
Jun Leng,
Altaf Ehtisham,
Yi Hu,
Qianshan Ding,
Hui Xu,
Shengwu Liu,
Jin Wang,
Dean G Tang, Qiuping Zhang
[show abstract]
[hide abstract]
ABSTRACT: We have previously demonstrated that the CCR9/CCL25 signaling pathway plays an important role in drug resistance in human acute T-lymphocytic leukemia (T-ALL) by inducing activation of ERM protein with polarized distribution in T-ALL cell line MOLT4. However, the mechanism of action of the activated ERM protein in the drug resistance of MOLT4 cells induced by CCL25 remains uncharacterized. Here we investigated the mechanism of CCR9/CCL25-initiated drug resistance in CCR9-high-expressing T-ALL cells. Our results showed that 1) the function of P-gp was increased after treatment with CCL25; 2) P-gp colocalized and co-immunoprecipitated with p-ERM and F-actin in CCL25 treated cells; and 3) ERM-shRNA conferred drug sensitivity coincident with release of ERM interactions with P-gp and F-actin after treatment with CCL25. These data suggest it is pivotal that P-gp associate with the F-actin cytoskeleton through p-ERM in CCR9/CCL25 induced multidrug resistance of T-ALL cells. Strategies aimed at inhibiting P-gp-F-actin cytoskeleton association may be helpful in increasing the efficiency of therapies in T-ALL.
PLoS ONE 01/2013; 8(1):e52384. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The epithelial-mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms and has recently been implicated in promoting carcinoma invasion and metastasis. Besides their therapeutic effects, accumulating evidences suggest that chemotherapeutic agents also induced EMT and enhanced the malignancy of treated cancer cells; however, the mechanism(s) still remains unclear. Here, we investigated the role of β-catenin signaling in doxorubicin (Dox)-induced EMT in human gastric cancer cell line BGC-823. We found that the transient treatment of Dox induced EMT and enhanced the in vitro migration ability of cancer cells. We also found that β-catenin signaling was activated upon Dox treatment. Inhibition of β-catenin by indomethacin (Indo) or siRNA suppressed Dox-induced EMT and decreased cancer cell migration ability. Our results showed that β-catenin signaling was critical to Dox-induced EMT. Indo and other β-catenin inhibitors may have a potential implication in prevention of gastric cancer metastasis.
Tumor Biology 10/2012; · 1.94 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Multidrug resistance (MDR) and multi-organ infiltration are the major obstacles to the successful treatment of leukemia. It is known that the drug efflux protein, P-glycoprotein (P-gp), and inhibitors of apoptosis proteins (IAPs) are involved in the MDR of leukemic cells, but their roles in leukemia infiltration have not been clearly elucidated. In this study, leukemic cell lines K562 and HL60 and their MDR variants K562R and HL60R have been used to analyze their infiltrative ability. MDR variants display enhanced invasion compared with parental cells. Results from xenografts in SCID (severe combined immunodeficiancy) mice are consistent with these in vitro observations. Furthermore, P-gp and cIAP are overexpressed and co-localize with protein kinase C-ε (PKC-ε) in MDR variants. Our study shows that overexpression of P-gp and cIAP may enhance the infiltration of leukemic cells.
Leukemia & lymphoma 07/2011; 52(7):1302-11. · 2.40 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have previously demonstrated that CCR9 plays a pivotal role in drug resistance and invasion in human acute T-lymphocytic leukemia (T-ALL). In this study, we investigated whether the MOLT4 cells, which naturally express CCR9 at high levels, can be successfully killed by the specific ligand, CCL25 fused to Pseudomonas exotoxin 38 (PE38) toxin. Our results demonstrated that CCL25-PE38 was able to specifically kill MOLT4 cells via apoptosis induction, and suppress the growth of CCR9(+) tumors. This work shows that CCR9 high-expressing human T-ALL cells can be successfully killed by delivering PE38 toxin fused to the ligand CCL25.
Leukemia research 02/2011; 35(9):1254-60. · 2.36 Impact Factor
-
Li Zhang,
Beibei Yu,
Meng Hu,
Zhan Wang,
Dongying Liu,
Xiaoling Tong,
Jun Leng,
Beibei Zhou,
Yi Hu,
Ranran Wu,
Qianshan Ding, Qiuping Zhang
[show abstract]
[hide abstract]
ABSTRACT: Our previous research has revealed that binding of the chemokine CCL25 to the CCR9 provides chemotactic cues guiding leukemic cells to specific tissues and organs. The RhoA-ROCK pathway might be involved in cancer migration. The purpose of this study was to explore the role of the RhoA-ROCK-MLC axis in leukemic cell migration following exposure to CCL25. The results showed that CCL25 could increase the amount of the GTPase RhoA and activate MLC in MOLT4 cells in a time-dependent manner. C3 exoenzyme and Y-27632 could block MOLT4 cell migration and chemotaxis. Thus, the RhoA-ROCK-MLC axis might play an important role in MOLT4 cell metastasis induced by CCL25.
Leukemia research 01/2011; 35(1):103-9. · 2.36 Impact Factor
-
Beibei Zhou,
Jun Leng,
Meng Hu,
Li Zhang,
Zhan Wang,
Dongying Liu,
Xiaoling Tong,
Beibei Yu,
Yi Hu,
Chaohua Deng,
Yanping Liu, Qiuping Zhang
[show abstract]
[hide abstract]
ABSTRACT: Chemokines and their corresponding receptors participate in transmigration of leukemic cells. ERM (ezrin/radixin/moesin) protein family act as linkers between the plasma membrane and the cytoskeleton and are key component in tumor metastasis. In this study we used the CCR9-expressing acute T lymphocytic cell line MOLT4 as a model and assesssed their morphological and functional changes in response to CCL25. The pseudopodium formed and ERM translocated from the cytoplasm to the cell membrane following treatment with CCL25. Ezrin silencing by miRNA showed that ezrin plays important roles in the polarization and invasive behaviour of MOLT4 cells.
Leukemia research 06/2010; 34(6):769-76. · 2.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In previous study, we found that the chemokine receptor 9 (CCR9) was highly expressed on CD4+ T cells from patients with T-cell lineage acute lymphocytic leukemia (T-ALL) and mediated leukemia cell infiltration and metastasis. Combined use of interleukin 2 (IL-2) and IL-4 promoted the internalization of CCR9 and therefore attenuated leukemia cell infiltration and metastasis. In this study, we preliminarily investigated the mechanism of internalization of CCR9 on MOLT4 cell model (a human leukemia T-cell line, naturally expresses CCR9) and found that IL-2 upregulated the cell surface expression of IL-4Ralpha (CD124) greatly, whereas IL-4 had no significant influence on alpha (CD25) and beta subunits (CD122) of IL-2R. Moreover, specific inhibitors, such as staurosporine, H89 and heparin, inhibited internalization of CCR9, which indicated a role of protein kinase C (PKC) and G protein-coupled kinase 2 (GRK2), respectively. Furthermore, GRK2 was upregulated and translocated to cell membrane in IL-2 and IL-4 treated cells which indicated that PKC could be a prerequisite for GRK2 activity.
Cellular & molecular immunology 07/2009; 6(3):181-9. · 2.99 Impact Factor
-
Chunsong Hu,
Jei Xiong,
Linjei Zhang,
Baojun Huang, Qiuping Zhang,
Qun Li,
Mingzhen Yang,
Yaou Wu,
Qun Wu,
Qian Shen,
Qingping Gao,
Kejian Zhang,
Zhimin Sun,
Junyan Liu,
Youxin Jin,
Jinquan Tan
[show abstract]
[hide abstract]
ABSTRACT: We investigated CD19+CD34+ and CD19+CD34- B cells from cord blood (CB) and typical patients with B cell lineage acute and chronic lymphocytic leukemia (B-ALL and B-CLL) in terms of expression and functions of CXCR5/CXCL13 and CCR7/CCL19. CXCR5 and CCR7 were selectively frequent expressed on B-ALL, B-CLL and CB CD19+CD34+ B cells, but not on CD19+CD34- B cells. Instead of induction of impressive chemotactic responsiveness, CXCL13 and CCL19 together induced significant resistance to TNF-alpha-mediated apoptosis in B-ALL and B-CLL but not CB CD19+CD34+ B cells. B-ALL and B-CLL CD19+CD34+ B cells expressed elevated level of Paternally Expressed Gene 10 (PEG10), and CXCL13 and CCL19 together significantly up-regulated PEG10 expression in the cells. We found that CXCL13 and CCL19 together by means of activation of CXCR5 and CCR7 up-regulated PEG10 expression and function, subsequent stabilized caspase-3 and caspase-8 in B-ALL and B-CLL CD19+CD34+ B cells, and rescued the cells from TNF-alpha-mediated apoptosis. We suggested that normal lymphocytes, especially naive B and T cells, utilized CXCR5/CXCL13 and CCR7/CCL19 for migration, homing, maturation, and cell homeostasis as well as secondary lymphoid tissues organogenesis. Meanwhile certain malignant cells took advantages of CXCR5/CXCL13 and CCR7/CCL19 for infiltration, resistance to apoptosis, and inappropriate proliferation.
Cellular & molecular immunology 09/2004; 1(4):280-94. · 2.99 Impact Factor
