Related Experiment Video

Updated: May 17, 2026

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
08:19

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

Published on: July 20, 2019

Mitochondrial-associated nitric oxide synthase activity inhibits cytochrome c oxidase: implications for breast cancer

Suvajit Sen1, Brian Kawahara, Gautam Chaudhuri

  • 1Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. ssen@mednet.ucla.edu

Free Radical Biology & Medicine
|October 24, 2012
PubMed

Insights

Mitochondrial nitric oxide synthase (NOS) activity in breast cancer cells promotes proliferation by increasing hydrogen peroxide and inhibiting protein phosphatase 2A, leading to sustained Akt and ERK1/2 signaling.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Nitric oxide synthase (NOS) activity is present in tumor cells, but its role in proliferation is unclear.
  • Triple-negative breast tumor patients expressing NOS have a worse prognosis.
  • NOS activity in breast cancer cell lines ZR-75-30 and BT-474 is associated with mitochondria.

Purpose of the Study:

  • To elucidate the role of mitochondrial-associated NOS activity in breast cancer cell proliferation.
  • To investigate the signaling pathways affected by mitochondrial NOS in cancer cells.

Main Methods:

  • Comparing NOS activity in malignant (ZR-75-30, BT-474) and benign (MCF-12F) breast cells.
  • Using inhibitors of NO synthesis and soluble guanylate cyclase (ODQ).
  • Assessing effects on cell proliferation, cytochrome c oxidase, hydrogen peroxide production, protein phosphatase 2A activity, and Akt/ERK1/2 phosphorylation.

Main Results:

  • Mitochondrial-associated NOS activity was detected in malignant cells but not benign cells.
  • Inhibiting NO synthesis decreased proliferation in malignant cells but not benign cells.
  • Mitochondrial NOS inhibited cytochrome c oxidase, increased hydrogen peroxide, inhibited protein phosphatase 2A, and maintained Akt/ERK1/2 phosphorylation, promoting proliferation.

Conclusions:

  • Mitochondrial-associated NOS activity drives breast cancer cell proliferation through a cGMP-independent pathway.
  • This pathway involves increased hydrogen peroxide, inhibition of protein phosphatase 2A, and sustained Akt/ERK1/2 signaling.
  • Targeting mitochondrial NOS may offer a therapeutic strategy for breast cancer.

Related Concept Videos

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...
Mitochondrial Membranes01:45

Mitochondrial Membranes

A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
The Electron Transport Chain01:30

The Electron Transport Chain

The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
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...