Depletion of NBR1 in urothelial carcinoma cells enhances rapamycin‐induced apoptosis through impaired autophagy and mitochondrial dysfunction. Issue 11 (11th July 2019)

• Record Type: Journal Article
• Authors: Kim, Myeong Joo; Hwang, Gwang Yong; Cho, Min Ji; Chi, Byung Hoon; Park, Serk In; Chang, In Ho; Whang, Young Mi
• Is Part Of: Journal of cellular biochemistry. Volume 120:Issue 11(2019)
• Page Start: 19186
• Page End: 19201
• Publication Date: 2019-07-11
• Subjects: AMPK -- autophagy -- bladder cancer -- mitochondrial biogenesis -- NBR1 -- rapamycin; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.29248
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: 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. Abstract : The inactivation of NBR1 leads to impair the autophagy elongation pathway in urothelial carcinoma of the bladder, and thus NBR1 loss may define an important subset of tumors with enhanced rapamycin sensitivity.