Abstract
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.
Highlights
MM is the second most common hematological malignancy affecting millions of people worldwide [1]
By using our cMYC/KRAS12V-transduced adoptive plasmacytoma mouse model, we found that Gls1 is involved in PCT pathogenesis
To investigate whether Gls1 was involved in PCT pathogenesis, we employed the cMYC/KRAS12Vtransduced adopted PCT mouse model
Summary
MM is the second most common hematological malignancy affecting millions of people worldwide [1]. Targeting the Warburg effect is becoming a useful strategy for preventing or stopping the development of cancer [5, 6]. Previous studies have demonstrated that many genes are associated with the Warburg effect, including those involved in glycolysis and glutamine metabolism [7, 8]. As the essential enzyme for glutamine metabolism, GLS1 is a potentially critical target for cancer therapy. GLS1 is highly expressed in many types of cancers, including MM, and previous studies have shown that inhibition of glutamine metabolism impairs MM cell survival and overcomes drug resistance in vitro [12,13,14], but the detailed mechanism in vivo are still insufficient
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