Silence of MCL-1 upstream signaling by shRNA abrogates multiple myeloma growth

Experimental Hematology & Oncology

Jiusheng Deng³  Pengbo Liu²  Di Wu¹  Mengchang Wang¹ 

[1] Department of Hematology, First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, China;Department of Global Health, Rollins School of Public Health, Emory University, Atlanta 30322, USA;Department of Hematology & Medical Oncology, Winship Cancer Institute, School of Medicine, Emory University, Atlanta 30322, USA

关键词: MAPK;    PI3K;    STAT3;    MCL-1;    shRNA;    Multiple myeloma;   

Others  :  1135299
DOI  :  10.1186/2162-3619-3-27

 received in 2014-09-11, accepted in 2014-11-04,  发布年份 2014

【 摘 要 】

Objectives

Multiple myeloma (MM) is an incurable B-cell cancer with accumulated clonal abnormal plasma cells in bone marrow of patients. MCL-1 (myeloid cell leukemia sequence 1) protein is an anti-apoptotic molecule in MM cells and regulated by pro-inflammatory cytokine IL-6 and downstream signaling molecules STAT3, PI3K and MAPK. The purpose of this study is to investigate the effect of STAT3, PI3K and MAPK gene silence on MCL-1 expression in human MM cells and the consequence of cell survival.

Methods

Lentivirus small hairpin RNA (shRNA) interference techniques were utilized to knock down STAT3, PI3K or MAPK genes. Gene and protein expression was quantified by quantitative real-time PCR and Western Blot. MM cell apoptosis was examined by annexin-V FITC/propidium iodide staining.

Results

Efficient silence of STAT3, PI3K, MAPK1 or MAPK2 gene robustly abrogated IL-6 enhanced MCL-1 expression and suppressed MM cell growth. Silencing STAT3 gene inhibited PI3K expression, silencing PI3K markedly abrogated STAT3 and MAPK production. Inhibition of MAPK2 gene by shMAPK2 suppressed STAT3, PI3K and MAPK1 expression in the cells. Silencing of STAT3, PI3K and MAPK2 together completely blocked MCL-1 expression in MM cells.

Conclusion

There is a syngeneic effect among the three independent STAT3, PI3K and MAPK2 survival-signaling pathways related to MCL-1 expression in MM cells. shRNAs silencing of STAT3, PI3K and MAPK2 together could provide an effective strategy to treat MM.

【 授权许可】

   
2014 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

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