In Greek mythology, the Moirai or the Fates are a group of three weaving goddesses who assign individual destinies to mortals at birth. An individual’s fate was set, and not even Zeus was able to recall their decisions. However, unlike in Greek mythology, the fate of whether a cancer cell lives or dies is not fully known or understood. Now, using a fruit fly model, researchers from the RIKEN Center for Biosystems Dynamics Research (BDR) report they have discovered molecular events that determine the fate of cancer cells and this knowledge allowed them to intervene and prevent the growth of cells that become cancerous.

Their findings were published in the journal eLife in a paper titled, “Methionine restriction breaks obligatory coupling of cell proliferation and death by an oncogene Src in Drosophila.”

“Oncogenes often promote cell death as well as proliferation. How oncogenes drive these diametrically opposed phenomena remains to be solved,” wrote the researchers. “A key question is whether cell death occurs as a response to aberrant proliferation signals or through a proliferation-independent mechanism.”

The international research group was led by Sa Kan Yoo, MD, PhD, team leader, at RIKEN BDR. The team focused on the oncogene Src and investigated how cell proliferation and cell death are regulated in Drosophila.

The researchers demonstrated that Src does not induce cell death as a result of cell proliferation, but it drives both processes independently and at the same time.

By inhibiting the function of specific genes through RNA interference, the researchers discovered that the gene p38 was involved in cell proliferation and the gene JNK was involved in cell death. They also discovered a gene called slpr that simultaneously activates p38 and JNK.

“How oncogenes simultaneously promote cell death and cell proliferation has been controversial,” said Yoo. “Our major finding was that the oncogene Src promotes cell death and cell proliferation via parallel pathways.”

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

One concept for treating cancer takes advantage of the fail-safe mechanism by inhibiting cell proliferation, but not cell death. Now that the team has identified p38 activation as a key role leading to cell proliferation, they could make this concept a reality. The researchers also discovered that p38’s activity can be controlled by nutrients in the diet.

Investigating the relationship between the food fed to fly larvae and cell proliferation, the researchers observed that reducing the amount of the amino acid methionine in the diet prevented p38-controlled oncogenesis.

“We were excited to find that manipulating the amount of dietary methionine can affect cell proliferation but not cell death,” explained Yoo. “Currently we don’t know whether our finding in flies will translate to cases of human cancer. But, we speculate that it will in particular cases because some human cancers also activate the Src gene.

“We are curious to know how general the mechanism is that we found here. Aside from 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,” concluded Yoo.

The new findings can provide insights into how human cancers develop and open a door of opportunity for dietary therapy for cancer.

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