Related Experiment Videos

Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2

Shannon P Fortin1, Matthew J Ennis, Benjamin A Savitch

  • 1Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.

Molecular Cancer Research : MCR
|October 29, 2009
PubMed

Insights

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes malignant glioma cell survival by activating Akt2. Akt2 gene expression correlates with glioma grade and inversely with patient survival, suggesting it as a therapeutic target.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Malignant gliomas are aggressive primary brain tumors with poor patient outcomes.
  • The TWEAK/Fn14 pathway is implicated in glioma cell survival.
  • Previous studies linked TWEAK to NF-kappaB activation and BCL-X(L) upregulation.

Purpose of the Study:

  • Investigate the role of Akt and BAD in TWEAK-mediated glioma cell survival.
  • Determine the specific Akt isoform involved in TWEAK signaling.
  • Assess the clinical relevance of Akt2 in glioma progression and survival.

Main Methods:

  • Glioma cell culture and treatment with TWEAK.
  • Western blotting to detect protein phosphorylation (Akt, BAD).
  • Small interfering RNA (siRNA) to deplete Akt1, Akt2, or BAD.
  • Assessment of cell survival and apoptosis.
  • Analysis of AKT2 gene expression in patient samples.
  • Immunohistochemistry for Akt2 and Fn14 expression.

Main Results:

  • TWEAK treatment phosphorylates Akt1 and Akt2 in glioma cells.
  • BAD phosphorylation at serine 136 is dependent on Akt2.
  • siRNA-mediated Akt2 depletion abrogates TWEAK-stimulated glioma cell survival.
  • TWEAK protects cells from apoptosis even after BAD depletion.
  • AKT2 gene expression increases with glioma grade and correlates inversely with patient survival.
  • Akt2 expression positively correlates with Fn14 expression in glioblastoma.

Conclusions:

  • The TWEAK-Fn14 axis promotes glioblastoma cell survival, partly through Akt2 activation.
  • Akt2 plays a critical role in TWEAK-mediated cell protection, independent of BAD phosphorylation.
  • Akt2 is a potential therapeutic target in malignant gliomas, as its expression correlates with tumor grade and poor prognosis.

Related Concept Videos

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...
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...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
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...
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...