Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition

被引：129

作者：

Cea, Michele ^{[1
,2
,3
]}

Cagnetta, Antonia ^{[1
,2
,4
]}

Fulciniti, Mariateresa ^{[1
,2
]}

Tai, Yu-Tzu ^{[1
,2
]}

Hideshima, Teru ^{[1
,2
]}

Chauhan, Dharminder ^{[1
,2
]}

Roccaro, Aldo ^{[1
,2
]}

Sacco, Antonio ^{[1
,2
]}

Calimeri, Teresa ^{[1
,2
]}

Cottini, Francesca ^{[1
,2
]}

Jakubikova, Jana ^{[1
,2
]}

Kong, Sun-Young ^{[1
,2
,5
]}

Patrone, Franco ^{[3
]}

Nencioni, Alessio ^{[3
]}

Gobbi, Marco ^{[4
]}

Richardson, Paul ^{[1
,2
]}

Munshi, Nikhil ^{[1
,2
]}

Anderson, Kenneth C. ^{[1
,2
]}

机构：

[1] Harvard Univ, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Sch Med, Boston, MA 02115 USA

[2] Harvard Univ, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, Sch Med, Boston, MA 02115 USA

[3] Azienda Osped Univ San Martino IST, Ist Ricovero & Cura Carattere Sci, Dept Internal Med, Genoa, Italy

[4] Azienda Osped Univ San Martino IST, Ist Ricovero & Cura Carattere Sci, Dept Hematol & Oncol, Genoa, Italy

[5] Natl Canc Ctr, Res Inst & Hosp, Goyang, South Korea

来源：

BLOOD | 2012年 / 120卷 / 17期

基金：

美国国家卫生研究院;

关键词：

NICOTINAMIDE ADENINE-DINUCLEOTIDE; ANTITUMOR-ACTIVITY; MOLECULAR-MECHANISMS; MAMMALIAN TARGET; BONE-MARROW; DEPLETION; RAPAMYCIN; CANCER; NAMPT; PHOSPHORIBOSYLTRANSFERASE;

D O I：

10.1182/blood-2012-03-416776

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Malignant cells have a higher nicotinamide adenine dinucleotide (NAD(+)) turnover rate than normal cells, making this biosynthetic pathway an attractive target for cancer treatment. Here we investigated the biologic role of a rate-limiting enzyme involved in NAD(+) synthesis, Nampt, in multiple myeloma (MM). Nampt-specific chemical inhibitor FK866 triggered cytotoxicity in MM cell lines and patient MM cells, but not normal donor as well as MM patients PBMCs. Importantly, FK866 in a dose-dependent fashion triggered cytotoxicity in MM cells resistant to conventional and novel anti-MM therapies and overcomes the protective effects of cytokines (IL-6, IGF-1) and bone marrow stromal cells. Nampt knockdown by RNAi confirmed its pivotal role in maintenance of both MM cell viability and intracellular NAD(+) stores. Interestingly, cytotoxicity of FK866 triggered autophagy, but not apoptosis. A transcriptional-dependent (TFEB) and independent (PI3K/mTORC1) activation of autophagy mediated FK866 MM cytotoxicity. Finally, FK866 demonstrated significant anti-MM activity in a xenograft-murine MM model, associated with down-regulation of ERK1/2 phosphorylation and proteolytic cleavage of LC3 in tumor cells. Our data therefore define a key role of Nampt in MM biology, providing the basis for a novel targeted therapeutic approach. (Blood. 2012;120(17):3519-3529)

引用

页码：3519 / 3529

页数：11

共 45 条

[41] NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response [J].