PMID- 38228583
OWN - NLM
STAT- MEDLINE
DCOM- 20240118
LR  - 20240125
IS  - 2041-4889 (Electronic)
VI  - 15
IP  - 1
DP  - 2024 Jan 16
TI  - Targeting POLRMT by a first-in-class inhibitor IMT1 inhibits osteosarcoma cell 
      growth in vitro and in vivo.
PG  - 57
LID - 10.1038/s41419-024-06444-9 [doi]
LID - 57
AB  - Osteosarcoma (OS) is a highly aggressive form of bone cancer that predominantly 
      affects adolescents and young adults. In this study, we have undertaken an 
      investigation into the potential anti-OS cell activity of IMT1 (inhibitor of 
      mitochondrial transcription 1), a first-in-class inhibitor of RNA polymerase 
      mitochondrial (POLRMT). IMT1 exhibited a profound inhibitory effect on cell 
      survival, proliferation, cell cycle progression, and migration in primary and 
      immortalized OS cells. Furthermore, this POLRMT inhibitor elicited apoptosis in 
      the OS cells, without, however, inducing cytotoxicity in human osteoblasts or 
      osteoblastic cells. IMT1 disrupted mitochondrial functions in OS cells, resulting 
      in mitochondrial depolarization, oxidative injury, lipid peroxidation, and ATP 
      reduction in OS cells. Silencing POLRMT using targeted shRNA closely mimicked the 
      actions of IMT1 and exerted potent anti-OS cell activity. Importantly, IMT1's 
      effectiveness was diminished in POLRMT-silenced OS cells. Subsequent 
      investigations revealed that IMT1 suppressed the activation of the Akt-mammalian 
      target of rapamycin (mTOR) cascade in OS cells. IMT1 treatment or POLRMT 
      silencing in primary OS cells led to a significant reduction in Akt1-S6K-S6 
      phosphorylation. Conversely, it was enhanced upon POLRMT overexpression. The 
      restoration of Akt-mTOR activation through the introduction of a constitutively 
      active S473D mutant Akt1 (caAkt1) mitigated IMT1-induced cytotoxicity in OS 
      cells. In vivo, oral administration of IMT1 robustly curtailed the growth of OS 
      xenografts in nude mice. Furthermore, IMT1 suppressed POLRMT activity, impaired 
      mitochondrial function, repressed Akt-mTOR activation, and induced apoptosis 
      within xenograft tissues. Collectively, these findings underscore the potent 
      growth-inhibitory effects attributed to IMT1 via targeted POLRMT inhibition. The 
      utilization of this POLRMT inhibitor carries substantial therapeutic promise in 
      the context of OS treatment.
CI  - (c) 2024. The Author(s).
FAU - Kong, Yang
AU  - Kong Y
AD  - Department of Orthopedics, the First Affiliated Hospital of Soochow University, 
      Suzhou, China.
AD  - Department of Orthopedics, The First People's Hospital of ChuZhou, ChuZhou, 
      China.
FAU - Li, Xiangrong
AU  - Li X
AD  - Department of Pharmacy, Kongjiang Hospital of Yangpu District, Shanghai, China.
FAU - Zhang, Huanle
AU  - Zhang H
AD  - Department of Radiotherapy, Suzhou Ninth People's Hospital, Suzhou, China.
FAU - Fu, Bin
AU  - Fu B
AD  - Department of Orthopedics, the First Affiliated Hospital of Soochow University, 
      Suzhou, China.
FAU - Jiang, Hua-Ye
AU  - Jiang HY
AD  - Department of Orthopedics, the First Affiliated Hospital of Soochow University, 
      Suzhou, China.
FAU - Yang, Hui-Lin
AU  - Yang HL
AUID- ORCID: 0000-0002-9459-7981
AD  - Department of Orthopedics, the First Affiliated Hospital of Soochow University, 
      Suzhou, China. suzhouspine@163.com.
AD  - Orthopedic Institute, Medical College, Soochow University, Suzhou, China. 
      suzhouspine@163.com.
FAU - Dai, Jin
AU  - Dai J
AUID- ORCID: 0009-0001-9270-5205
AD  - Department of Orthopedics, Suzhou Wujiang District Children's Hospital, Suzhou, 
      China. drdaijinwj9@163.com.
LA  - eng
GR  - Z2022044/National Natural Science Foundation of China (National Science 
      Foundation of China)/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20240116
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.7.6 (POLRMT protein, human)
RN  - EC 2.7.7.6 (DNA-Directed RNA Polymerases)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Adolescent
MH  - Young Adult
MH  - Humans
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Mice, Nude
MH  - Cell Line, Tumor
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Osteosarcoma/genetics
MH  - Sirolimus/pharmacology
MH  - Apoptosis
MH  - *Bone Neoplasms/drug therapy/metabolism
MH  - Cell Proliferation
MH  - Mitochondria/metabolism
MH  - Mammals
MH  - DNA-Directed RNA Polymerases
PMC - PMC10791695
COIS- The authors declare no competing interests.
EDAT- 2024/01/17 00:42
MHDA- 2024/01/18 06:42
PMCR- 2024/01/16
CRDT- 2024/01/16 23:13
PHST- 2023/09/18 00:00 [received]
PHST- 2024/01/05 00:00 [accepted]
PHST- 2024/01/03 00:00 [revised]
PHST- 2024/01/18 06:42 [medline]
PHST- 2024/01/17 00:42 [pubmed]
PHST- 2024/01/16 23:13 [entrez]
PHST- 2024/01/16 00:00 [pmc-release]
AID - 10.1038/s41419-024-06444-9 [pii]
AID - 6444 [pii]
AID - 10.1038/s41419-024-06444-9 [doi]
PST - epublish
SO  - Cell Death Dis. 2024 Jan 16;15(1):57. doi: 10.1038/s41419-024-06444-9.