Study On Targeting Inhibition Of TCTP In The Treatment Of Acute Myeloid Leukemia

Leukemia is a common life-threatening malignant disease in hematopoietic system.At present,the major treatment in the clinic for leukemia is still chemotherapy,which is lack of specificity and can produce many kinds of side effects,leading to relapse,drug resistance and other phenomena.It is therefore necessary to explore new therapeutic strategies for leukemia with lower toxicity and higher efficiency.In the previous work,by using two-dimensional electrophoresis(2-DE)and mass spectrometry,we systematically analysed the protein expression profiles of U937 cells before and after RIG-G(retinoic acid-induced gene G,RIG-G)expression.We found that TCTP(translationally controlled tumor protein,TCTP)is one of the major down-regulated proteins after RIG-G expression.It has been known that TCTP is a ubiquitous protein in eukaryotic cells,which plays important roles in cell proliferation,apoptosis,etc.Moreover,TCTP has been considered to be closely related to the occurrence and development of many kinds of tumors.In the first part of this thesis,we established an inducible AML(acute myeloid leukemia,AML)subline which could stably inhibit TCTP expression,as well as its corresponding control.Our results showed that interfering the expression of TCTP could significantly cause the growth inhibition and apoptosis in AML cells.More over,we injected the above AML sublines into NOD-SCID mice,compared with the control,the subcutaneous xenograft tumor manifested the smaller volume and the lighter weight in the mice injected with TCTP-interfered AML cells.As also,by the analysis of immunohistochemistry and immunofluorescence,we found that the expression of Ki67,a proliferation-promoting protein,was significantly lower,while the positive rate of TUNEL,a marker of apoptosis,was dramaticlly higher in those xenograft tumors with TCTP-interfered than in control.These results further indicated that targeting inhibition of TCTP expression could induce cell apoptosis and suppress cell proliferation in AML cells,and might be expected to become a new way for leukemia treatment.In this study,we also detected the protein level of TCTP in some primary bone marrow cells isolated from AML patients,and found that the TCTP level was generally higher in the bone marrow of AML patients by compared with non-leukemia bone marrow samples.These data suggestted that TCTP might function as a new biomarker for AML diagnosis and prognosis in clinic.In the second part of this thesis,we studied the biological effects of sertraline,a TCTP targeting drug,in AML cells.Sertraline is one of the most commonly antidepressant drugs in clinic.It has been reported that sertraline could bind directly to TCTP and facilitate the secretion of the latter,finally decreasing its intracellular concentration.In this study,we provided evidences that sertraline had potent antiproliferative activity not only in AML cell lines but also in the fresh leukemia cells from AML patients,and could induce cell death through both apoptosis and autophagy pathways.Moreover,we found that autophagy pathway could to some degree promote sertraline-induced apoptosis and cell growth inhibition.Our results provided experimental evidences for further investigation of TCTP as a new target for leukemia treatment,and would furnish some perspectives for novel therapeutic strategies in leukemia.