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Melittin exerts antitumorigenic effects in human MM1.S multiple myeloma cells through the suppression of AKT/mTOR/S6K1/4E-BP1 signaling cascades

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Abstract

Although melittin, a water-soluble 26-amino acid peptide derived from bee venom of Apis mellifera, is known to exert anti-proliferative effects on various tumor cell lines, very little is known about its potential molecular mechanism(s) of action. In the present study, we investigated the effects of melittin on the AKT/mTOR/S6K1/4E-BP1 activation, associated gene products, cellular proliferation, and apoptosis in several tumor cells. We found that melittin inhibited both constitutive phosphorylation of AKT and mTOR and exerted a significant time-dependent anti-proliferative effect on MM1.S cells as compared to other types of tumor cells. Indeed, melittin clearly suppressed the constitutive activation of AKT/mTOR/S6K1/4E-BP1 signaling cascades, which correlated with the induction of apoptosis. Melittin can cause broad-spectrum inhibition of AKT/mTOR/S6K1/4E-BP1 axes in multiple myeloma cells when compared with various pharmacological AKT/mTOR inhibitors. Aberrant AKT activation by pcDNA3-myr-HA-AKT1 plasmid could not prevent the observed suppressive effect of melittin on constitutive mTOR, S6K1, and 4E-BP1 activation and overexpression of Bcl-2 also attenuated melittin-mediated apoptosis in the cells. Our results clearly indicate that melittin can interfere with multiple signaling cascades involved in carcinogenesis and thereby used as a potential drug candidate for both the prevention and treatment of cancer.

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Acknowledgments

This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korean Ministry of Education, Science and Technology (MoEST) (No. 2011–0006220).

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  1. Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul, 130-701, Republic of Korea

    Chulwon Kim, Dong Sub Kim, Dongwoo Nam, Sung-Hoon Kim, Bum Sang Shim & Kwang Seok Ahn

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  1. Chulwon Kim
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  2. Dong Sub Kim
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  4. Sung-Hoon Kim
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Correspondence to Kwang Seok Ahn.

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Chulwon Kim, Dong Sub Kim and Dongwoo Nam contributed equally to this study.

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Kim, C., Kim, D.S., Nam, D. et al. Melittin exerts antitumorigenic effects in human MM1.S multiple myeloma cells through the suppression of AKT/mTOR/S6K1/4E-BP1 signaling cascades. Orient Pharm Exp Med 15, 33–44 (2015). https://doi.org/10.1007/s13596-014-0172-4

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