2. Academic Validation
  3. Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

  • Cell Death Dis. 2018 Sep 24;9(10):996. doi: 10.1038/s41419-018-1065-0.
Sara Iachettini 1,  Daniela Trisciuoglio 2 3,  Dante Rotili 4,  Alessia Lucidi 4,  Erica Salvati 1,  Pasquale Zizza 1,  Luca Di Leo 5,  Donatella Del Bufalo 2,  Maria Rosa Ciriolo 5,  Carlo Leonetti 6,  Clemens Steegborn 7,  Antonello Mai 4,  Angela Rizzo 8,  Annamaria Biroccio 9
Affiliations

Affiliations

  • 1 Oncogenomic and Epigenetic Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
  • 2 Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
  • 3 Institute of Molecular Biology and Pathology, CNR National Research Council, Via degli Apuli 4, 00185, Rome, Italy.
  • 4 Department of Drug Chemistry and Technologies, Sapienza University, Piazzale Aldo Moro 5, 00185, Rome, Italy.
  • 5 Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy.
  • 6 SAFU, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
  • 7 Department of Biochemistry, University of Bayreuth, 95440, Bayreuth, Germany.
  • 8 Oncogenomic and Epigenetic Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. angela.rizzo@ifo.gov.it.
  • 9 Oncogenomic and Epigenetic Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy. annamaria.biroccio@ifo.gov.it.
PMID: 30250025 DOI: 10.1038/s41419-018-1065-0
Abstract

Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase Sirtuin family, which plays a key role in Cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and Autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 Activator. Our data demonstrated that UBCS039 induced a time-dependent activation of Autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of Autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate Autophagy. At the molecular level, SIRT6-mediated Autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced Autophagy, suggesting that ROS burst had a key role in upstream events leading to Autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an Autophagy Inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 Activator, thereby providing a proof of principle that modulation of the Enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z