Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway

Sadahira,Ken; Sagawa,Morihiko; Nakazato,Tomonori; Uchida,Hideo; Ikeda,Yasuo; Okamoto,Shinichiro; Nakajima,Hideaki; Kizaki,Masahiro

doi:10.3892/ijo.2014.2652

Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway

Authors:
- Ken Sadahira
- Morihiko Sagawa
- Tomonori Nakazato
- Hideo Uchida
- Yasuo Ikeda
- Shinichiro Okamoto
- Hideaki Nakajima
- Masahiro Kizaki
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Affiliations: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, Department of Hematology, Saitama Medical Center, Saitama Medical University, Saitama 350-8550, Japan, Department of Hematology, Yokohama Municipal Hospital, Kanagawa 240-8555, Japan, Department of Laboratory Medicine, Tokyo Electric Power Company Hospital, Tokyo 160-0016, Japan
Published online on: September 15, 2014 https://doi.org/10.3892/ijo.2014.2652
Pages: 2278-2286

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Abstract

Multiple myeloma (MM) is a clonal plasma cell disorder affecting the immune system with various systemic symptoms. MM remains incurable even with high dose chemotherapy using conventional drugs, thus necessitating development of novel therapeutic strategies. Gossypol (Gos) is a natural polyphenolic compound extracted from cotton plants, and has been shown to possess anti-neoplastic activity against various tumors. Recent studies have shown that Gos is an inhibitor for Bcl-2 or Bcl-XL acting as BH3 mimetics that interfere interaction between pro-apoptotic BH3-only proteins and Bcl-2/Bcl-XL. Since most of the patients with MM overexpress Bcl-2 protein, we considered Gos might be a promising therapeutic agent for MM. We herein show that Gos efficiently induced apoptosis and inhibited proliferation of the OPM2 MM cell line, in a dose- and time-dependent manner. Gos induced activation of caspase-3 and cytochrome c release from mitochondria, showing mitochondrial dysfunction pathway is operational during apoptosis. Further investigation revealed that phosphorylation of Bcl-2 at serine-70 was attenuated by Gos treatment, while protein levels were not affected. In addition, Mcl-1 was downregulated by Gos. Interestingly, phosphorylation of JAK2, STAT3, ERK1/2 and p38MAPK was inhibited by Gos-treatment, indicating that Gos globally suppressed interleukin-6 (IL-6) signals. Moreover, JAK2 inhibition mimicked the effect of Gos in OPM2 cells including Bcl-2 dephosphorylation and Mcl-1 downregulation. These results demonstrated that Gos induces apoptosis in MM cells not only through displacing BH3-only proteins from Bcl-2, but also through inhibiting IL-6 signaling, which leads to Bcl-2 dephosphorylation and Mcl-1 downregulation.

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