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TSC Research Article Summaries: Kidneys

Human TSC-associated renal angiomyolipoma cells are hypersensitive to ER stress

Brian J Siroky , Hong Yin , Justin T. Babcock , Lu Lu , Anna R. Hellmann , Bradley P. Dixon , Lawrence A Quilliam , John J Bissler
Am J Physiol Renal Physiol. 2012 Sep 15;303(6):F831-44
DOI: 10.1152/ajprenal.00441.2011

What is the topic?

Effect of cellular stress on human renal angiomyolipomas.

What did the researchers hope to learn?

Mechanistic (or mammalian) target of rapamycin (mTOR) is a protein that regulates cell growth and other cellular functions.  It is known that angiomyolipomas shrink with treatment with mTOR inhibitors such as sirolimus (Rapamune) or everolimus (Afinitor), but they often grow back after treatment is stopped. Researchers believe this is because mTOR inhibitors are cytostatic towards angiomyolipomas (i.e. stunt cell growth) instead of cytotoxic (kill cells). The researchers in this study wanted to uncover cell pathways that could be targeted to kill cells, instead of just slowing them down.

Who/what was studied?

Cells grown from human angiomyolipomas lacking TSC2 (TSC2 null) were compared to normalized cells expressing TSC2 to demonstrate that TSC2 null angiomyolipoma cells experience cellular stress of the endoplasmic reticulum (ER), an organelle in the cell that is responsible for protein folding and transport. In addition, researchers evaluated fixed tissue sections from human angiolipomas. The researchers also wanted to see if they could amplify ER stress in human angiolipoma cells by using an agent that inhibits the proteasome, which is a cellular unit that acts as a “trash can” for improperly folded proteins, and by doing so, induce cell death.

How was the study conducted?

Microscopic and molecular studies were performed to discern if TSC2 null human angiolipoma cells and human angiolipoma tissue are inhibited, but not killed by mTOR inhibition and to see if they demonstrate enhanced ER stress and are susceptible to death by proteasome inhibition.

What did the researchers find?

  1. There is molecular and microscopic evidence of ER stress in TSC2 null human angiomyolipoma cells and human angiomyolipoma tissue.
  2. Proteasome inhibition kills human angiomyolipoma cells.
  3. Proteasome inhibition and mTOR inhibition work together to kill human angiomyolipoma cells better than either agent alone.

What were the limitations of the study?

This study is promising, but the results are still preliminary because the experiments were performed in a laboratory on samples taken from the body (in vitro) rather than on live patients or animal models (in vivo).

What do the results mean for you?

Renal angiolipomas in TSC patients may respond better to combination therapy with a proteasome inhibitor and an mTOR inhibitor than an mTOR inhibitor alone. More studies are needed to determine whether this approach is beneficial.

This summary was written by Neera Nathan, third-year medical student at the George Washington University, Washington DC and Doris Duke Clinical Research Scholar studying the dermatologic manifestations of TSC  in the laboratory of Thomas Darling, MD, PhD (December 2014).