PMID- 31297862
OWN - NLM
STAT- MEDLINE
DCOM- 20200908
LR  - 20200908
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Linking)
VI  - 120
IP  - 11
DP  - 2019 Nov
TI  - Depletion of NBR1 in urothelial carcinoma cells enhances rapamycin-induced 
      apoptosis through impaired autophagy and mitochondrial dysfunction.
PG  - 19186-19201
LID - 10.1002/jcb.29248 [doi]
AB  - Rapamycin is well-recognized in the clinical therapeutic intervention for 
      patients with cancer by specifically targeting mammalian target of rapamycin 
      (mTOR) kinase. Rapamycin regulates general autophagy to clear damaged cells. 
      Previously, we identified increased expression of messenger RNA levels of NBR1 
      (the neighbor of BRCA1 gene; autophagy cargo receptor) in human urothelial cancer 
      (URCa) cells, which were not exhibited in response to rapamycin treatment for 
      cell growth inhibition. Autophagy plays an important role in cellular physiology 
      and offers protection against chemotherapeutic agents as an adaptive response 
      required for maintaining cellular energy. Here, we hypothesized that loss of NBR1 
      sensitizes human URCa cells to growth inhibition induced by rapamycin treatment, 
      leading to interruption of protective autophagic activation. Also, the potential 
      role of mitochondria in regulating autophagy was tested to clarify the mechanism 
      by which rapamycin induces apoptosis in NBR1-knockdown URCa cells. NBR1-knockdown 
      URCa cells exhibited enhanced sensitivity to rapamycin associated with the 
      suppression of autophagosomal elongation and mitochondrial defects. Loss of NBR1 
      expression altered the cellular responses to rapamycin treatment, resulting in 
      impaired ATP homeostasis and an increase in reactive oxygen species (ROS). 
      Although rapamycin treatment-induced autophagy by adenosine 
      monophosphate-activated protein kinase (AMPK) phosphorylation in NBR1-knockdown 
      cells, it did not process the conjugated form of LC3B-II after activation by 
      unc-51 like autophagy-activating kinase 1 (ULK1). NBR1-knockdown URCa cells 
      exhibited rather profound mitochondrial dysfunctions in response to rapamycin 
      treatment as evidenced by Deltapsim collapse, ATP depletion, ROS accumulation, and 
      apoptosis activation. Therefore, our findings provide a rationale for rapamycin 
      treatment of NBR1-knockdown human urothelial cancer through the regulation of 
      autophagy and mitochondrial dysfunction by regulating the AMPK/mTOR signaling 
      pathway, indicating that NBR1 can be a potential therapeutic target of human 
      urothelial cancer.
CI  - (c) 2019 Wiley Periodicals, Inc.
FAU - Kim, Myeong Joo
AU  - Kim MJ
AD  - Department of Urology, College of Medicine, Chung-Ang University, Seoul, Republic 
      of Korea.
FAU - Hwang, Gwang Yong
AU  - Hwang GY
AD  - Department of Urology, College of Medicine, Chung-Ang University, Seoul, Republic 
      of Korea.
FAU - Cho, Min Ji
AU  - Cho MJ
AD  - Department of Urology, College of Medicine, Chung-Ang University, Seoul, Republic 
      of Korea.
FAU - Chi, Byung Hoon
AU  - Chi BH
AD  - Department of Urology, College of Medicine, Chung-Ang University, Seoul, Republic 
      of Korea.
FAU - Park, Serk In
AU  - Park SI
AD  - Department of Biochemistry and Molecular Biology, Korea University College of 
      Medicine, Seoul, Republic of Korea.
FAU - Chang, In Ho
AU  - Chang IH
AD  - Department of Urology, College of Medicine, Chung-Ang University, Seoul, Republic 
      of Korea.
FAU - Whang, Young Mi
AU  - Whang YM
AUID- ORCID: 0000-0002-9571-4078
AD  - Department of Urology, College of Medicine, Chung-Ang University, Seoul, Republic 
      of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190711
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (NBR1 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Apoptosis/*drug effects/genetics
MH  - Autophagy/*drug effects/genetics
MH  - Cell Line, Tumor
MH  - Gene Deletion
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*deficiency/genetics
MH  - Mitochondria/genetics/*metabolism/pathology
MH  - Neoplasm Proteins/*deficiency/metabolism
MH  - Sirolimus/*pharmacology
MH  - Urinary Bladder Neoplasms/drug therapy/genetics/*metabolism/pathology
OTO - NOTNLM
OT  - AMPK
OT  - NBR1
OT  - autophagy
OT  - bladder cancer
OT  - mitochondrial biogenesis
OT  - rapamycin
EDAT- 2019/07/13 06:00
MHDA- 2020/09/09 06:00
CRDT- 2019/07/13 06:00
PHST- 2018/12/10 00:00 [received]
PHST- 2019/06/05 00:00 [accepted]
PHST- 2019/07/13 06:00 [pubmed]
PHST- 2020/09/09 06:00 [medline]
PHST- 2019/07/13 06:00 [entrez]
AID - 10.1002/jcb.29248 [doi]
PST - ppublish
SO  - J Cell Biochem. 2019 Nov;120(11):19186-19201. doi: 10.1002/jcb.29248. Epub 2019 
      Jul 11.