Gossypol induces apoptosis of multiple myeloma cells through the JUN-JNK pathway

Multiple myeloma (MM) is one of the most common hematologic neoplastic diseases. Gossypol was once used as a male contraceptive but is considered a novel antitumor agent. This study aimed to reveal the gossypol-induced apoptosis mechanism and its hub genes. Gossypol-induced MM cell apoptosis is concentration- and time-dependent. Of a total of 532 differentially expressed genes, 273 genes were upregulated and 259 genes were downregulated in gossypol-treated MM cells. Through KEGG and WGCNA analyses, the apoptosis-associated module was identified, and JUN was identified as the hub gene. The expression of the JUN protein product c-Jun was downregulated in MM cell lines compared to that in normal plasma cells. High-risk MM patients had a lower expression of JUN. High-expression JUN group patients had a lower risk of death. JUN overexpression in MM cells induced potent cell death and growth inhibition by a caspase-dependent apoptotic mechanism. DR5 is one of the upstream receptors of the JNK pathway, and shRNA knockdown of DR5 can partially reverse gossypol-induced apoptosis. A total of 1017 genes were coexpressed with JUN in MM patients. These genes are mainly involved in other JNK-associated signaling pathways, such as the IL6, EGF and PDGF signaling pathways. In conclusion, JUN is identified as the hub gene in gossypol-induced apoptosis, and gossypol can activate caspase-dependent apoptosis through the JNK pathway by targeting c-Jun and other JNK-associated pathways. DR5 and IL6 are also involved in this mechanism.