Related Experiment Videos

SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production

E L Bell1, B M Emerling, S J H Ricoult

  • 1Paul F. Glenn Laboratory and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.

Oncogene
|March 2, 2011
PubMed

Insights

Mitochondrial sirtuin 3 (SirT3) suppresses tumor growth by reducing reactive oxygen species (ROS) and regulating hypoxia-inducible factor 1α (HIF-1α). Loss of SirT3 enhances cancer cell proliferation and tumorigenesis, while its overexpression inhibits tumor development.

Area of Science:

  • Cellular metabolism
  • Cancer biology
  • Mitochondrial function

Background:

  • Alterations in cellular metabolism are crucial for cancer development and progression.
  • Oncogene activation and tumor suppressor loss contribute to metabolic reprogramming in cancer.
  • Mitochondrial sirtuins, like SirT3, play roles in metabolic regulation and cellular homeostasis.

Purpose of the Study:

  • To investigate the role of mitochondrial sirtuin 3 (SirT3) as a tumor suppressor.
  • To determine the mechanisms by which SirT3 affects cancer cell proliferation and tumorigenesis.
  • To elucidate the relationship between SirT3, reactive oxygen species (ROS), and hypoxia-inducible factor 1α (HIF-1α) in cancer.

Main Methods:

  • Utilized short-hairpin RNA (shRNA) to knockdown SirT3 expression in primary mouse embryo fibroblasts (MEFs) and tumor cell lines.
  • Assessed cell proliferation, HIF-1α protein stabilization, and transcriptional activity under hypoxic conditions.
  • Employed xenograft mouse models to evaluate the impact of SirT3 modulation on tumorigenesis.
  • Administered N-acetyl cysteine (NAC) as an antioxidant in vivo.

Main Results:

  • SirT3 knockdown led to increased cell proliferation, enhanced HIF-1α stabilization, and augmented HIF-1α transcriptional activity under hypoxia.
  • SirT3 knockdown significantly increased tumorigenesis in xenograft models.
  • Administration of NAC abolished the increased tumorigenesis observed in SirT3-knockdown mice.
  • Overexpression of SirT3 inhibited HIF-1α stabilization and attenuated its transcriptional activity in hypoxia.
  • Overexpression of SirT3 reduced tumor growth in xenografts, even when induced post-tumor initiation.

Conclusions:

  • SirT3 functions as a tumor suppressor by suppressing ROS production and regulating HIF-1α.
  • The tumor-suppressive activity of SirT3 is mediated, at least in part, by its control over ROS and HIF-1α.
  • Targeting SirT3 or its downstream pathways presents a potential therapeutic strategy for cancer treatment.

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...