Starving ER+ breast cancer cells by blocking their amino acid transporter (necessary)

[Lani]

Research aims to starve breast cancer cells
[Medical College of Georgia]

AUGUSTA, Ga. - The most common breast cancer uses the most efficient, powerful food delivery system known in human cells and blocking that system kills it, researchers report.

This method of starving cancer cells could provide new options for patients, particularly those resistant to standard therapies such as tamoxifen, Georgia Health Sciences University researchers said.

Human estrogen receptor-positive breast cancer cells thriving in a Petri dish or transplanted onto mice die when exposed to a drug that blocks the transporter, called SLC6A14, said Dr. Vadivel Ganapathy, Chairman of GHSU's Department of Biochemistry and Molecular Biology.

"It basically starves the cancer cell," said Ganapathy, corresponding author of the study published in the Journal of Biological Chemistry. The transporter can carry 18 of the known 20 amino acids, fuel all cells need in some combination. Amino acids enable cells to make proteins, which they need to function and survive. The cell type determines its amino acid needs and delivery system. Rapidly growing, dividing estrogen receptor-positive breast cancer needs nearly every amino acid so it makes the smart choice of utilizing the transporter that can deliver the biggest load, Ganapathy said.

SLC6A14 is the only transporter known to carry all 10 essential amino acids, essential because the body can't make them so they have to be delivered via the bloodstream from food. The transporter also takes eight of the nonessential amino acids along for the ride, Ganapathy said.

And it is a fast ride. The transporter has three energy sources instead of the usual one or two, he said.

Interestingly, SLC6A14 is expressed at low levels in most of the body. "There are specialized features of this transport system which could be used by every cell to its advantage but they do not seem to do that. It's expressed only at low levels in normal tissues," Ganapathy noted. While that may seem like a loss for healthy cells, it bolsters the cancer-fighting potential for drugs that block SLC6A14 by making it a more specific cancer target. "Since the normal cells do not depend on this transporter, you can use a drug that selectively blocks it to target cancer cells" Ganapathy said.

The compound they used is alpha-methyl-DL-tryptophan, already used in humans for short periods when they are getting a PET scan in certain areas of the brain. When the researchers treated estrogen receptor-positive breast cancer cells with it or put it in the drinking water of the mice with the cells, rapid growth stopped and the cancer cells died. Further studies showed alpha-methyl-DL-tryptophan seemed to impact only cells expressing the SLC6A14 transport system. Even another type of breast cancer, estrogen receptor-negative, wasn't impacted.

Researchers are now determining the most potent version of the compound.

The research was supported by the National Institutes of Health.



ABSTRACT: SLC6A14 (ATB0,+), a highly concentrative and broad-specific amino acid transporter, is a novel and effective drug target for treatment of estrogen receptor-positive breast cancer
[Journal of Biological Chemistry]

SLC6A14, also known as ATB0,+, is an amino acid transporter with unique characteristics. It transports 18 of the 20 proteinogenic amino acids. However, this transporter is expressed only at low levels in normal tissues. Here we show that the transporter is upregulated specifically in estrogen receptor (ER)-positive breast cancer, demonstrable with primary human breast cancer tissues and human breast cancer cell lines. SLC6A14 is an estrogen/ER target. The transport features of SLC6A14 include concentrative transport of leucine (an activator of mTOR), glutamine (essential for nucleotide biosynthesis and substrate for glutaminolysis), and arginine (an essential amino acid for tumor cells), suggesting that ER-positive breast cancer cells upregulate SLC6A14 to meet their increased demand for these amino acids. Consequently, treatment of ER-positive breast cancer cells in vitro with α-methyl-DL-tryptophan (α-MT), a selective blocker of SLC6A14, induces amino acid deprivation, inhibits mTOR, and activates autophagy. Prolongation of the treatment with α-MT causes apoptosis. Addition of an autophagy inhibitor (3-methyladenine) during α-MT treatment also induces apoptosis. These effects of α-MT are specific to ER-positive breast cancer cells, which express the transporter. The ability of α-MT to cause amino acid deprivation is significantly attenuated in MCF7 cells, an ER-positive breast cancer cell line, when SLC6A14 is silenced with shRNA. In mouse xenograft studies, α-MT by itself is able to reduce the growth of the ER-positive ZR75.1 breast cancer cells. These studies identify SLC6A14 as a novel and effective drug target for the treatment of ER-positive breast cancer.

Experiments done with her2 negative cell lines--will try to read the original article and see if they tried any other cell lines eg BT474 which is ER+and her2+

[Rich66]

The compound they used is alpha-methyl-DL-tryptophan, already used in humans for short periods when they are getting a PET scan in certain areas of the brain.

Already being used..gotta love that.


Here is the full research paper:
http://www.jbc.org/content/early/201...11.229518.long

In conclusion, the present studies provide the proof-of-principle that SLC6A14 is a potential drug target for the treatment of ER-positive breast cancer. α-MT in itself represents a viable drug for this purpose. It could also serve as a lead compound for the design and development of more potent blockers of SLC6A14 for future use.

Article mentioning AMT and serotonin level monitoring via PET:

http://www.nature.com/jcbfm/journal/.../9590848a.html

Alpha-methyl-L-tryptophan (AMT) is an analog of tryptophan, the precursor of the neurotransmitter serotonin (5-HT, 5-hydroxytryptamine). For the past decade, Diksic and colleagues performed numerous studies of radiolabeled AMT in rats and dogs with the goal of validating AMT as a tracer for the measurement of the rate of sertonin synthesis in vivo in humans with positron emission tomography (PET).

In summary, we believe that the rat studies demonstrate unequivocably the presence of irreversible uptake of AMT. However, these studies also demonstrate that the serotonin synthesis component is a fraction of the irreversible uptake of the tracer (Fig. 5). Thus, although lacking properties for measuring the absolute synthesis rate, AMT uptake is useful as an index or capacity for serotonin synthesis.

This all begs the question of whether available anxiety/depression drugs or supplements that alter serotonin levels might be useful in this ER+ cancer equation.