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Serine racemase multifunctional enzyme could be key to beating CRC

Wed, 01/29/2020 - 09:58
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A team of researchers led by Osaka University has discovered an important new role for Serine racemase (SRR), is a multifunctional enzyme that carries out several different reactions in human cells including the conversion of L-serine into pyruvate, in cancer metabolism exposing the metabolic pathway as a viable target for novel anti-cancer therapies. The research, ‘Serine racemase enhances growth of colorectal cancer by producing pyruvate from serine’, was published in Nature Metabolism.

Researchers have long known that cancer cells display an altered metabolism that favours their growth, survival and metastasis. Colorectal cancer is one of the most common cancers worldwide but is particularly prevalent in developed countries where it is associated with certain dietary factors and a sedentary lifestyle. One of the hallmarks of colorectal cancer cells is an altered metabolism that is not associated with tumour-causing mutations.

"Pyruvate is known to have an important role in cancer metabolism," explained lead author of the study, Dr Kenji Ohshima. "However, no one had previously studied how pyruvate produced by SRR is involved in cancer metabolism."

Therefore, the researchers set out to examine what role, if any, SRR plays in the development of colorectal cancer. They found that SRR is much more abundant in colorectal cancer cells than in the surrounding tissues and that cancer cell lines with higher levels of SRR divide at a much faster rate.

"This was a really exciting discovery because it showed that SRR is involved in colorectal cancer cell proliferation,” explained Ohshima. “When we then looked more closely at the pathway as a whole, we found that pyruvate levels were decreased in a slow-growing SRR mutant colorectal cancer cell line, suggesting that the pyruvate produced by SRR enhances the proliferation of colorectal cancer cells. This result confirmed that the metabolic pathway is integral to the progression of colorectal cancer."

SRR-mediated dehydration of serine contributes to the pyruvate pool in colon cancer cells, maintains mitochondrial mass and leads to anti-apoptotic effect, resulting in enhancement of growth of colon cancer cells. (Credit: Osaka University)
SRR-mediated dehydration of serine contributes to the pyruvate pool in colon cancer cells, maintains mitochondrial mass and leads to anti-apoptotic effect, resulting in enhancement of growth of colon cancer cells. (Credit: Osaka University)

Given the obvious importance of SRR, the researchers then decided to test whether disruption of the metabolic pathway could prevent the progression of colorectal cancer. Astonishingly, not only did inhibition of SRR halt the growth of colorectal tumours in mice, it also improved the efficacy of currently available drugs used to treat colorectal cancer, causing a significant reduction in tumour size.

"There is still work to be done to confirm that our results translate into human cancer systems," added senior author of the study, Dr Eiichi Morii. "However, based on these preliminary results, we expect that future strategies targeting SRR will provide effective new therapies for the treatment of colorectal cancer."