Targeting glutaminase1 and synergizing with clinical drugs achieved more promising antitumor activity on multiple myeloma
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Qiang Qiu1, Mengyuan Li1, Linyu Yang1, Minghai Tang1, Li Zheng1, Fang Wang1, Huandi Qiu1, Cailing Liang1, Ning Li1, Dongni Yi2, Yuyao Yi2, Cong Pan1,4, Shengyong Yang1, Lijuan Chen1 and Yiguo Hu1,3
1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China
2 Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
3 Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
4 Guizhou Normal College, Guiyang, China
|Lijuan Chen,||email:||[email protected]|
|Yiguo Hu,||email:||[email protected]|
Keywords: glutaminase1; multiple myeloma; BPTES; cMYC/KRAS12V-transduced plasmacytoma; mouse model
Received: April 15, 2019 Accepted: September 10, 2019 Published: October 15, 2019
Multiple myeloma (MM) pathogenesis remains incompletely understood and biomarkers predicting treatment response still remain lacking. Here we describe the rational mechanisms of combining targeting glautaminase1 (GLS1) with other chemo-reagents for MM treatment. Gls1 is highly expressed cMYC/KRAS12V-drived plasmacytoma (PCT) cells. Down-regulation of Gls1 with miRNAi in cMYC/KRAS12V-expressing BaF3 cells prevented them from growing independence of interleukin 3 (IL3). By using our cMYC/KRAS12V-transduced adoptive plasmacytoma mouse model, we found that Gls1 is involved in PCT pathogenesis. Down-regulation of Gls1 significantly prolonged the survival of PCT recipients. Knockdown of Gls1 increased the expression of Cdkn1a and Cdkn1b and decreased the expression of some critical oncogenes for cancer cell survival, such as c-Myc, Cdk4, and NfκB, as well as some genes which are essential for MM cell survival, such as Irf4, Prdm1, Csnk1α1, and Rassf5. Combination of Gls1 inhibition with LBH589, Bortezomib, or Lenalidomide significantly impaired tumor growth in a MM xenograft mouse model. Our data strongly suggest that Gls1 plays an important role for MM pathogenesis and that combination of GLS1 inhibitor with other MM therapy agents could benefit to MM patients.
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