title: Mangiferin induces apoptosis in multiple myeloma cell lines by suppressing the activation of nuclear factor kappa B-inducing kinase.
abstract: Mangiferin is a naturally occurring glucosyl xanthone, which induces apoptosis in various cancer cells. However, the molecular mechanism underlying mangiferin-induced apoptosis has not been clarified thus far. Therefore, we examined the molecular mechanism underlying mangiferin-induced apoptosis in multiple myeloma (MM) cell lines. We found that mangiferin decreased the viability of MM cell lines in a concentration-dependent manner. We also observed an increased number of apoptotic cells, caspase-3 activation, and a decrease in the mitochondrial membrane potential. In addition, mangiferin inhibited the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated inhibitor kappa B (IκB) and increased the expression of IκB protein, whereas no changes were observed in the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase 1/2 (JNK1/2), and mammalian target of rapamycin (mTOR). The molecular mechanism responsible for mangiferin-induced inhibition of nuclear translocation of NF-κB was a decrease in the expression of phosphorylated NF-κB-inducing kinase (NIK). Moreover, mangiferin decreased the expression of X-linked inhibitor of apoptosis protein (XIAP), survivin, and Bcl-xL proteins. Knockdown of NIK expression showed results similar to those observed with mangiferin treatment. Our results suggest that mangiferin induces apoptosis through the inhibition of nuclear translocation of NF-κB by suppressing NIK activation in MM cell lines. Our results provide a new insight into the molecular mechanism of mangiferin-induced apoptosis. Importantly, since the number of reported NIK inhibitors is limited, mangiferin, which targets NIK, may be a potential anticancer agent for the treatment of MM.
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Takeda
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsubaki
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kino
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Iida
authors.affiliation: Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, Nara, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Imano
authors.affiliation: Laboratory of Pharmaceutical Organic Chemistry, School of Pharmacy, Kinki University, Kowakae, Higashi-Osaka, Japan.
authors.forename: Genzoh
authors.initials: G
authors.lastname: Tanabe
authors.affiliation: Laboratory of Pharmaceutical Organic Chemistry, School of Pharmacy, Kinki University, Kowakae, Higashi-Osaka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Muraoka
authors.affiliation: Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Satou
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan. Electronic address: nishida@phar.kindai.ac.jp.
authors.forename: Shozo
authors.initials: S
authors.lastname: Nishida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones; C013592:mangiferin; D051550:I-kappa B Kinase
keywords: Apoptosis; Mangiferin; Multiple myeloma; NF-κB; NIK