Depletion of NBR1 in urothelial carcinoma cells enhances rapamycin-induced apoptosis through impaired autophagy and mitochondrial dysfunction

Myeong Joo Kim, Gwang Yong Hwang, Min Ji Cho, Byung Hoon Chi, Serk In Park, In Ho Chang, Young Mi Whang

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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 Δψm 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.

Original languageEnglish
Pages (from-to)19186-19201
Number of pages16
JournalJournal of cellular biochemistry
Issue number11
Publication statusPublished - 2019 Nov 1

Bibliographical note

Funding Information:
This study was supported by the National Research Foundation (NRF) of the Republic of Korea. (NRF‐2016R1D1A1B03933826 and NRF‐2019R1I1A1A01061485 to YMW, NRF‐2018R1D1A1A02050248 to IHC, NRF‐ 2015R1C1A1A01051508 to SIP, and NRF‐2017R1D1A1B03031514 to BHC), the Korea Health Technology R&D Project (HI17C0710 to IHC), and the Ministry of Health and Welfare of the Republic of Korea (National R&D Program for Cancer, No. 1720140 to SIP)

Publisher Copyright:
© 2019 Wiley Periodicals, Inc.


  • AMPK
  • NBR1
  • autophagy
  • bladder cancer
  • mitochondrial biogenesis
  • rapamycin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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