Polyphyllin VII, a novel moesin inhibitor, suppresses cell growth and overcomes bortezomib resistance in multiple myeloma

• Published in: Cancer letters Vol. 537; p. 215647
• Main Authors: Wang, Haiqin, Xiao, Xiaojuan, Li, Zhenzhen, Luo, Saiqun, Hu, Lei, Yi, Hui, Xiang, Ruohong, Zhu, Yu, Wang, Yanpeng, Zhu, Lin, Xiao, Ling, Dai, Chongwen, Aziz, Abdul, Yuan, Lingli, Cui, Yajuan, Li, Ruijuan, Gong, Fanjie, Liu, Xifeng, Liang, Long, Peng, Hongling, Zhou, Hui, Liu, Jing
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.07.2022; Elsevier Limited
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Autophagy; beta Catenin - metabolism; Bone marrow; Bortezomib; Bortezomib - pharmacology; Bortezomib - therapeutic use; Bortezomib resistance; Cancer therapies; Cell cycle; Cell growth; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Inhibitor drugs; Libraries; Ligands; Malignancy; Microfilament Proteins; Moesin; Moesin inhibitor; Multiple myeloma; Multiple Myeloma - pathology; Natural products; Neoplasm Recurrence, Local - drug therapy; Polyphyllin; Proteasome inhibitors; Proteasome Inhibitors - pharmacology; Proteasome Inhibitors - therapeutic use; Proteasomes; Proteins; Saponins; Statistical analysis; Targeted cancer therapy; Therapeutic targets; Ubiquitin; Wnt protein; Wnt/β-catenin pathway; β-Catenin; MM; ERM; Bortezomib resistance; ABC; CI; Multiple myeloma; BTZ; DARTS; Polyphyllin; CETSA; SD; Moesin inhibitor; GEP; PP7; Wnt/β-catenin pathway; HD; SP; BMMC
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.215647

Multiple myeloma is a plasma cell malignancy, accounting for approximately 1% of new cancer cases. It is the second most common hematological malignancy. Novel clinical agents such as the proteasome inhibitor-bortezomib, have shown improved survival rates in recent decades. However, multiple myeloma remains incurable, as most patients eventually relapse and become refractory to current treatments. Therefore, there is an urgent need for developing new regimens to overcome the bortezomib resistance. Here, we screened a library of 2370 bioactives and found that polyphyllin VII selectively suppressed multiple myeloma cell growth in vitro and in vivo. We identified moesin, one of the critical regulators of the Wnt/β-catenin pathway, as a target of polyphyllin VII by drug affinity responsive target stability assay and cellular thermal shift assay. Polyphyllin VII binds to moesin and induces its degradation via the ubiquitin-proteasome pathway, thereby impairing the Wnt/β-catenin pathway activity and leading to a reduction in the side population cells to overcome bortezomib resistance. Our study identified polyphyllin VII as a promising compound and moesin as a potential diagnostic and therapeutic target for treating multiple myeloma. •1.Polyphyllin VII exhibits potent and selective anti-MM effect in vitro and in vivo.•The PP7 binding to moesin leads to a decrease in its protein levels resulting in the inhibition of the Wnt/β-catenin pathway.•PP7 reduces side population cells to overcome bortezomib resistance in multiple myeloma.