Abstract
The activated JAK2-STAT3 signaling pathway is a high risk factor for multiple myeloma (MM), a fatal malignancy of plasma cells. In the present study, SC09, a potential inhibitor of cholesterol absorption, was identified in a STAT3-targeted drug screen. SC09 suppressed the activation of STAT3 in a time-course and concentration-dependent manner but did not affect its family members STAT1 and STAT5. SC09 inhibited STAT3 transcriptional activity and downregulated the expression of STAT3-regulated genes. Further studies showed that SC09 selectively inhibited JAK2 activation but not other kinases including c-Src, ERK, p38 and mTOR that are all associated with STAT3 activation. Moreover, SC09 obviously induced MM cell death in vitro and delayed MM tumor growth in vivo. SC09-induced MM cell death was dependent on the endogenous STAT3 status, and this effect could be attenuated by enforced expression of STAT3. All the results collectively indicated that SC09 blocks the JAK2-STAT3 signaling thus displaying anti-MM activity. Given its well tolerance and anti-MM potency, SC09 is credited for further investigation as a promising drug for MM treatment.
Highlights
Multiple myeloma (MM) is a class of fatal and progressive hematological malignancy derived from plasma cells, the cells that produce antibodies
We focused on the small molecule compound SC09 (Figure 1A), a reported inhibitor of cholesterol absorption (International Patent Publication Number: WO2007/008529A2)
SC09 was preliminarily found to reduce the expression of luciferase under control of STAT3-recognition elements by the high throughput screen, which suggested that SC09 was probably an inhibitor of the STAT3 signaling pathway
Summary
Multiple myeloma (MM) is a class of fatal and progressive hematological malignancy derived from plasma cells, the cells that produce antibodies. Last decades have witnessed the progress in MM pathophysiology and in the development of drug discovery, there is no cure for this specific disease [2]. A panel of molecularly targeted anti-cancer drugs have been marketed and have been demonstrated to be effective in both complete remission and progression-free survival. A recent study found that suppression of the STAT3 signaling pathway by the tight junction protein 1 increases proteasome inhibitor sensitivity in MM cells [4]. A sequencing screen over 142 untreated MM patients revealed that STAT3-mutation contributes a statistically significantly shortened progression-free survival and overall survival in these patients [7]. We found the inhibitor of cholesterol absorption SC09 displays anti-MM activity by suppressing the JAK2-STAT3 signaling pathway
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