TRIP13 impairs mitotic checkpoint surveillance and is associated with poor prognosis in multiple myeloma.
AAA-ATPase TRIP13 is one of the chromosome instability gene recently established in multiple myeloma (MM), the second most common and incurable hematological malignancy. However, the specific function of TRIP13 in MM is largely unknown. Using sequential gene expression profiling, we demonstrated that high TRIP13 expression levels were positively correlated with progression, disease relapse, and poor prognosis in MM patients. Overexpressing human TRIP13 in myeloma cells prompted cell growth and drug resistance, and overexpressing murine TRIP13, which shares 93% sequence identity with human TRIP13, led to colony formation of NIH/3T3 fibroblasts in vitro and tumor formation in vivo. Meanwhile, the knockdown of TRIP13 inhibited myeloma cell growth, induced cell apoptosis, and reduced tumor burden in xenograft MM mice. Mechanistically, we observed that the overexpression of TRIP13 abrogated the spindle checkpoint and induced proteasome-mediated degradation of MAD2 primarily through the Akt pathway. Thus, our results demonstrate that TRIP13 may serve as a biomarker for MM disease development and prognosis, making it a potential target for future therapies.
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Yi
Y
Tao
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Guang
G
Yang
Shanghai Key Laboratory of Plant Functional Genomics and Resources, Shanghai Chenshan Botanical Garden, Shanghai 201602, China.|Shanghai Chenshan Plant Science Research Center, Chienes Academy of Sciences, Shanghai 201602, China.
Hongxing
H
Yang
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Dongliang
D
Song
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Liangning
L
Hu
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Bingqian
B
Xie
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Houcai
H
Wang
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Lu
L
Gao
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Minjie
M
Gao
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Hongwei
H
Xu
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Zhijian
Z
Xu
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Xiaosong
X
Wu
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Yiwen
Y
Zhang
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Weiliang
W
Zhu
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
Fenghuang
F
Zhan
Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Jumei
J
Shi
D000074183:ATPases Associated with Diverse Cellular Activities / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor; D059447:Cell Cycle Checkpoints / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D064246:Mad2 Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities; C575259:TRIP13 protein, human
MAD2; TRIP13; drug resistance; multiple myeloma; prognosis