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Background: Multiple myeloma (MM) is a hematological malignancy characterized by uncontrolled proliferation of plasma cells and is currently incurable. Despite advancements in therapeutic strategies, resistance to proteasome inhibitors, particularly bortezomib (BTZ), poses a substantial challenge to disease management. This study aimed to explore the efficacy of boanmycin, a novel antitumor antibiotic, in overcoming resistance to BTZ in MM. Methods: BTZ-resistant cells were generated over a period of at least 6 months by gradually increasing the concentration of BTZ. The viability of MM cell lines and patient bone marrow mononuclear cells (BMMCs) was measured via the CCK8 reagent. The protein levels of cleaved caspase 3, cleaved caspase 7, cleaved PARP, PARP, p-JNK, JNK, and γ-H2AX were analyzed through Western blot. Cellular morphology was observed via transmission electron microscopy. Colony formation ability was evaluated, and cell apoptosis and the cell cycle were detected through flow cytometry. Xenograft experiments were conducted to evaluate the growth of MM cells in vivo. Results: Our results demonstrated that boanmycin effectively inhibited cell proliferation and colony formation, and triggered apoptosis in both BTZ-sensitive and BTZ-resistant MM cells. The combination of boanmycin with BTZ had greater inhibitory effects than either drug alone. Furthermore, boanmycin significantly suppressed MM cell growth in immunodeficient mouse xenograft models without inducing distinct toxic side effects. Notably, boanmycin markedly killed patient-derived MM cells ex vivo. Mechanistically, boanmycin not only disrupts the cell cycle and causes DNA damage but also exerts its antitumor effects by inducing endoplasmic reticulum (ER) functional impairment. Conclusions: Our findings highlight the potential of boanmycin as a promising novel therapeutic option for treating MM, particularly in patients with BTZ resistance. [ABSTRACT FROM AUTHOR]

Holometabolous insects undergo morphological remodeling from larvae to pupae and to adults with typical changes in the cuticle; however, the mechanism is unclear. Using the lepidopteran agricultural insect Helicoverpa armigera, cotton bollworm, as a model, we revealed that the transcription factor RUNT-like (encoded by Runt-like) regulates the development of the pupal cuticle via promoting a pupal cuticle protein gene (HaPcp) expression. The HaPcp was highly expressed in the epidermis and wing during metamorphosis and was found being involved in pupal cuticle development by RNA interference (RNAi) analysis in larvae. Runt-like was also strongly upregulated in the epidermis and wing during metamorphosis. Knockdown of Runt-like produced similar phenomena, a failure of abdomen yellow envelope and wing formation, to those following HaPcp knockdown. The insect molting hormone 20-hydroxyecdysonen (20E) upregulated HaPcp transcription via RUNT-like. 20E upregulated Runt-like transcription via nuclear receptor EcR and the transcription factor FOXO. Together, RUNT-like and HaPCP are involved in pupal cuticle development during metamorphosis under 20E regulation. Author summary: Holometabolous insects develop pupal cuticle during metamorphosis; however, the mechanism is unclear. Using the lepidopteran agricultural insect Helicoverpa armigera, cotton bollworm, as a model, we revealed that the transcription factor RUNT-like regulates a pupal cuticle protein gene, HaPcp, expression therefore regulates the development of the pupal cuticle under insect molting hormone 20-hydroxyecdysonen (20E) regulation. HaPcp is an insect specific gene without homologue in humans, and the insect Runt-like is different from vertebrate, too. This work deeply addresses the mechanism that 20E regulates development of insect pupal cuticle and presents new gene targets to explore the new growth regulators to control the pest. [ABSTRACT FROM AUTHOR]