Diet therapy for cancer? Consumption of amino acids determines the fate of cancer cells

This image shows the imaginal disc of the wing of the fruit fly. Green cells are living, proliferating cells that express an Src oncogene. Magenta cells are dying cells due to expression of Src. Thus, Src simultaneously promotes proliferation (green) and cell death (magenta). Credit: RIKEN

A research group at the RIKEN Center for Biosystems Dynamics Research (BDR) has discovered molecular events that determine whether cancer cells live or die. Armed with this knowledge, they discovered that reduced consumption of a specific protein building block prevents the growth of cells that become cancerous. These results were published in the scientific journal eLife and open up the possibility of dietary therapy for cancer.

A tumor is a group of cancer cells that multiply or proliferate uncontrollably. Tumors originate from individual cells which become cancerous when the genes that cause cells to proliferate are overactivated. However, since these genes, called oncogenes, often also cause cell death, activating a single oncogene in a cell is not enough for it to become a cancer cell. This phenomenon is considered to be a “fail-safe” mechanism that prevents cells from easily turning into cancer. In order for a cell to go through the cracks and become cancerous, several other oncogenes, as well as cancer suppressor genes, must be turned on in a multi-step process. The details of this process have been the subject of the new study.

The international research group led by Sa Kan Yoo at RIKEN BDR focused on the Src oncogene and investigated how cell proliferation – oncogenesis – and cell death are regulated in the fruit fly. They showed that Src does not induce cell death as a result of cell proliferation, but rather drives both processes independently and simultaneously. By inhibiting the function of specific genes by RNA interference, the team found that the p38 gene was involved in cell proliferation and the JNK gene was involved in cell death. In addition, they discovered a gene called slpr which simultaneously activates p38 and JNK. “How oncogenes simultaneously promote cell death and cell proliferation has been controversial,” Yoo explains. “Our main finding is that the Src oncogene promotes cell death and cell proliferation through parallel pathways.”

A cancer treatment concept takes advantage of the intrinsic safety mechanism by inhibiting cell proliferation, but not cell death. To do this, we need to know the molecular actors involved in the process. Once the team identified p38 activation as a key step leading to cell proliferation, they realized they could make this concept a reality. After studying what else we know about p38, they realized that its activity can be controlled by the nutrients in the diet.

They then set out to test this hypothesis by studying the relationship between the food given to fly larvae and cell proliferation. They discovered that reducing the amount of amino acid methionine in the diet prevented oncogenesis controlled by p38. “We were delighted to discover that manipulating the amount of dietary methionine can affect cell proliferation but not cell death,” Yoo explains. “Currently, we don’t know if our finding in flies will result in cancer cases in humans. But, we assume that this will be the case in special cases because some human cancers also activate the Src gene.

“We’re curious how general the mechanism is that we’ve found here. In addition to the Src signaling pathway, we also found that slpr can mediate the signaling pathways controlled by other oncogenes. Finding out how this happens is our next goal.

Since the process of oncogenesis is known to be the same in fruit flies and mammals, the new findings may help explain how human cancers grow.

Reference: “Methionine restriction disrupts the obligatory coupling of cell proliferation and death by an Src oncogene in Drosophila” by Hiroshi Nishida, Morihiro Okada, Lynna Yang, Tomomi Takano, Sho Tabata, Tomoyoshi Soga, Diana M Ho , Jongkyeong Chung, Yasuhiro Minami and Sa Kan Yoo, April 27, 2021, eLife.
DOI: 10.7554 / eLife.59809

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