Sirtuin Family Members Selectively Regulate Autophagy in Osteosarcoma and Mesothelioma Cells in Response to Cellular Stress

Our plain-English summary of Sirtuin Family Members Selectively Regulate Autophagy in Osteosarcoma and Mesothelioma Cells in Response to Cellular Stress, by R. Garva, C. Thepmalee, U. Yasamut, et al (Frontiers in Oncology, 2019).

The study

• Authors: R. Garva, C. Thepmalee, U. Yasamut, S. Sudsaward, A. Guazzelli, R. Rajendran, N. Tongmuang, S. Khunchai, P. Meysami, T. Limjindaporn, P.T. Yenchitsomanus, L. Mutti, M. Krstic-Demonacos, C. Demonacos
• Journal: Frontiers in Oncology
• Published: 2019;9:949
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The class III NAD+ dependent deacetylases-sirtuins (SIRTs) link transcriptional regulation to DNA damage response and reactive oxygen species generation thereby modulating a wide range of cellular signaling pathways. Here, the contribution of SIRT1, SIRT3, and SIRT5 in the regulation of cellular fate through autophagy was investigated under diverse types of stress. The effects of sirtuins' silencing on cell survival and autophagy was followed in human osteosarcoma and mesothelioma cells exposed to DNA damage and oxidative stress. Our results suggest that the mitochondrial sirtuins SIRT3 and 5 are pro-proliferative under certain cellular stress conditions and this effect correlates with their role as positive regulators of autophagy. SIRT1 has more complex role which is cell type specific and can affect autophagy in both positive and negative ways. The mitochondrial sirtuins (SIRT3 and SIRT5) affect both early and late stages of autophagy, whereas SIRT1 acts mostly at later stages of the autophagic process. Investigation of potential crosstalk between SIRT1, SIRT3, and SIRT5 revealed several feedback loops and a significant role of SIRT5 in regulating SIRT3 and SIRT1. Results presented here support the notion that sirtuin family members play important as well as differential roles in the regulation of autophagy in osteosarcoma vs. mesothelioma cells exposed to DNA damage and oxidative stress, and this can be exploited in increasing the response of cancer cells to chemotherapy.

Copyright © 2019 Garva, Thepmalee, Yasamut, Sudsaward, Guazzelli, Rajendran, Tongmuang, Khunchai, Meysami, Limjindaporn, Yenchitsomanus, Mutti, Krstic-Demonacos and Demonacos.

In plain English

This was a laboratory study of human cancer cells grown in culture. It was not a study of people, and it did not involve asbestos. The authors used one osteosarcoma (bone cancer) cell line, U2OS, and two mesothelioma cell lines, Mero-14 and REN. They silenced three proteins called sirtuins (SIRT1, SIRT3 and SIRT5). They then stressed the cells with rotenone, etoposide or resveratrol and measured cell survival and markers of autophagy, the process by which cells break down their own damaged parts. In U2OS cells, silencing SIRT1 increased survival in all conditions tested, while silencing SIRT3 or SIRT5 reduced survival with etoposide. In Mero-14 cells, silencing SIRT3 reduced survival with resveratrol. In REN cells, silencing had no significant effect, though survival trended downward without SIRT3 or SIRT5. Where significant effects were found, the sirtuins mostly raised autophagy markers. Most of their effects on each other's levels originated from SIRT5. The authors concluded that selectively targeting these sirtuins could be a basis for new strategies to increase cancer cells' response to chemotherapy. They added that the role of microenvironmental conditions requires further investigation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on human cancer cell lines
• Who was studied: Human cell lines: osteosarcoma U2OS and mesothelioma Mero-14 and REN; no human subjects
• Exposure: No asbestos or fiber exposure was studied. Cells had SIRT1, SIRT3 or SIRT5 silenced with siRNA and were treated with rotenone, etoposide or resveratrol (for example 10 µM for 24 h).
• Main results:
  • In U2OS osteosarcoma cells, SIRT1 silencing increased cell viability in all conditions tested
  • In U2OS cells, SIRT3 and SIRT5 silencing decreased cell viability with etoposide treatment
  • In Mero-14 mesothelioma cells, viability decreased when SIRT3 was silenced and cells were treated with resveratrol
  • In REN mesothelioma cells, sirtuin silencing had no significant effect on viability, though a downward trend was seen with SIRT3 and SIRT5 silencing
  • The sirtuins affected each other's protein levels, and most of these feedback loops originated from SIRT5
  • Where significant effects were seen, the sirtuins mostly had positive effects on the autophagy markers beclin-1 and the LC3II/LC3I ratio. The exception was etoposide-treated REN cells, where SIRT1 had a negative effect on the LC3II/LC3I ratio.
  • In U2OS cells measured by flow cytometry, SIRT3 silencing inhibited autophagy with etoposide or resveratrol
• The authors' conclusion: The authors concluded that SIRT1, SIRT3 and SIRT5 play distinct roles in regulating autophagy in these cell lines. They stated that selectively targeting them could be a basis for new strategies to increase response to chemotherapy.
• Limitations the authors state:
  • The sirtuins regulate each other, especially through SIRT5, which must be considered when interpreting experiments that silence a single sirtuin
  • The influence of microenvironmental conditions on sirtuin activity and autophagy requires further investigation

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Reactive Oxygen Species (ROS), Oxidative Stress, Chemotherapy.

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