PMID- 28912885
OWN - NLM
STAT- MEDLINE
DCOM- 20180705
LR  - 20220408
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 7
IP  - 14
DP  - 2017
TI  - Brusatol-Mediated Inhibition of c-Myc Increases HIF-1alpha Degradation and Causes 
      Cell Death in Colorectal Cancer under Hypoxia.
PG  - 3415-3431
LID - 10.7150/thno.20861 [doi]
AB  - HIF-1 (hypoxia-inducible factor-1) regulates the expression of ~100 genes 
      involved in angiogenesis, metastasis, tumor growth, chemoresistance and 
      radioresistance, underscoring the growing interest in targeting HIF-1 for cancer 
      control. In the present study, we investigated the molecular mechanisms 
      underlying brusatol-induced HIF-1alpha degradation and cell death in colorectal 
      cancer under hypoxia (0.5% O(2)). Under hypoxia, pretreatment of cancer cells 
      with brusatol increased HIF-1alpha degradation and cancer cell death in a 
      dose-dependent manner. This effect was mediated by activation of prolyl 
      hydroxylases (PHDs), as evidenced by the block of brusatol-induced HIF-1alpha 
      degradation and cancer cell death by both pharmacological inhibition and 
      siRNA-mediated knockdown of PHDs. In addition, a ferrous iron chelator 
      (2,2'-bypyridyl) blocked brusatol-induced degradation of HIF-1alpha and cancer cell 
      death in hypoxia by inhibiting PHD activation. We further found that brusatol 
      inhibited c-Myc expression, and showed that overexpression of c-Myc prevented 
      brusatol-induced degradation of HIF-1alpha and cancer cell death by increasing 
      mitochondrial ROS production and subsequent ROS-mediated transition of ferrous 
      iron to ferric iron. Consistent with these results, treatment of tumor-bearing 
      mice with brusatol significantly suppressed tumor growth by promoting 
      PHD-mediated HIF-1alpha degradation. Collectively, our results suggest that 
      brusatol-mediated inhibition of c-Myc/ROS signaling pathway increases HIF-1alpha 
      degradation by promoting PHD activity and induces cell death in colorectal cancer 
      under hypoxia.
FAU - Oh, Eun-Taex
AU  - Oh ET
AD  - Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 
      22212, Republic of Korea.
AD  - Hypoxia-related Disease Research Center, College of Medicine, Inha University, 
      Incheon 22212, Republic of Korea.
FAU - Kim, Chan Woo
AU  - Kim CW
AD  - Department of Microbiology, College of Medicine, Inha University, Incheon 22212, 
      Republic of Korea.
FAU - Kim, Ha Gyeong
AU  - Kim HG
AD  - Department of Microbiology, College of Medicine, Inha University, Incheon 22212, 
      Republic of Korea.
FAU - Lee, Jae-Seon
AU  - Lee JS
AD  - Department of Molecular Medicine, College of Medicine, Inha University, Incheon 
      22212, Republic of Korea.
FAU - Park, Heon Joo
AU  - Park HJ
AD  - Hypoxia-related Disease Research Center, College of Medicine, Inha University, 
      Incheon 22212, Republic of Korea.
AD  - Department of Microbiology, College of Medicine, Inha University, Incheon 22212, 
      Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170811
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Quassins)
RN  - 0 (Reactive Oxygen Species)
RN  - 14907-98-3 (brusatol)
RN  - EC 1.14.11.- (Prolyl Hydroxylases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - *Apoptosis
MH  - Cell Hypoxia
MH  - Colorectal Neoplasms/drug therapy/*metabolism
MH  - HCT116 Cells
MH  - HT29 Cells
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Prolyl Hydroxylases/metabolism
MH  - *Proteolysis
MH  - Proto-Oncogene Proteins c-myc/antagonists & inhibitors/*metabolism
MH  - Quassins/*pharmacology/therapeutic use
MH  - Reactive Oxygen Species/metabolism
PMC - PMC5596433
OTO - NOTNLM
OT  - Brusatol
OT  - Cell death
OT  - Colorectal cancer
OT  - HIF-1alpha
OT  - Hypoxia.
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2017/09/16 06:00
MHDA- 2018/07/06 06:00
PMCR- 2017/01/01
CRDT- 2017/09/16 06:00
PHST- 2017/05/04 00:00 [received]
PHST- 2017/06/20 00:00 [accepted]
PHST- 2017/09/16 06:00 [entrez]
PHST- 2017/09/16 06:00 [pubmed]
PHST- 2018/07/06 06:00 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - thnov07p3415 [pii]
AID - 10.7150/thno.20861 [doi]
PST - epublish
SO  - Theranostics. 2017 Aug 11;7(14):3415-3431. doi: 10.7150/thno.20861. eCollection 
      2017.