Rapamycin enhances growth inhibition on urothelial carcinoma cells through LKB1 deficiency-mediated mitochondrial dysregulation.
Young Mi WhangMyeong Joo KimMin Ji ChoHoyub YoonYoung Wook ChoiTae-Hyoung KimIn Ho ChangPublished in: Journal of cellular physiology (2018)
Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has significant potential for application in the treatment of urothelial carcinoma (URCa) of the bladder. Previous studies have shown that regulation of the AMP-activated serine/threonine protein kinase (AMPK)-mTOR signaling pathway enhances apoptosis by inducing autophagy or mitophagy in bladder cancer. Alteration of liver kinase B1 (LKB1)-AMPK signaling leads to mitochondrial dysfunction and the accumulation of autophagy-related proteins as a result of mitophagy, resulting in enhanced cell sensitivity to drug treatments. Therefore, we hypothesized that LKB1 deficiency in URCa cells could lead to increased sensitivity to rapamycin by inducing mitochondrial defect-mediated mitophagy. To test this, we established stable LKBI-knockdown URCa cells and analyzed the effects of rapamycin on their growth. Rapamycin enhanced growth inhibition and apoptosis in stable LKB1-knockdown URCa cells and in a xenograft mouse model. In spite of the stable downregulation of LKB1 expression, rapamycin induced AMPK activation in URCa cells, causing loss of the mitochondrial membrane potential, ATP depletion, and ROS accumulation, indicating an alteration of mitochondrial biogenesis. Our findings suggest that the absence of LKB1 can be targeted to induce dysregulated mitochondrial biogenesis by rapamycin treatment in the design of novel therapeutic strategies for bladder cancer.
Keyphrases
- induced apoptosis
- cell cycle arrest
- oxidative stress
- protein kinase
- signaling pathway
- endoplasmic reticulum stress
- cell death
- pi k akt
- mouse model
- skeletal muscle
- cell proliferation
- emergency department
- mesenchymal stem cells
- spinal cord injury
- poor prognosis
- dna damage
- diabetic rats
- single cell
- high glucose
- combination therapy
- risk assessment
- nlrp inflammasome
- replacement therapy