Researchers find a protein inducing liver tumor cells death

Cristina G. Pedraz/ DICYT Researchers at the Instituto de Biomedicina (Ibiomed), Universidad de León, Spain, in cooperation with scientist from Universität Mainz (Germany), have made further progress on studies linked to melatonin (a natural occurring human compound) effects on apoptosis (process of programmed cell death) on liver tumor cells. Specifically, the team led by José Luis Mauriz has found that therapeutic melatonin levels increase apoptosis without damaging normal cells through FoxO3a, a protein able to get into cell nucleus and induce the expression of another pro-apoptotic protein called Bim.

The study was recently published in the British Journal of Cancer and paves the way to therapies for the most common liver tumor: hepatocellular carcinoma, the fifth most reported worldwide and the second in mortality rate after five years of progression.

According to José Luis Mauriz, this breakthrough belongs to the Ibiomed research area on liver cancer. “For several years we have worked with different substances, melatonin is one of them; it is a hormone naturally synthesized by animals and when its levels are normal, it has antioxidant and biological rhythm maintenance properties.”, he explains.

The team is focused on the effects this hormone has on the liver, where it has a primarily antioxidant function. When they began to work with this substance in human liver tumor cells, they found melatonin was able to induce apoptosis, conserving normal cells. “Usually, these tumor cells are characterized by two different but complementary aspects: on one hand, cell cycle is deregulated, cell division occurs faster; on the other hand, apoptosis, or programmed cell death is also deregulated, which makes them virtually immortal.”

When therapeutic doses of melatonin were given, they found tumor cells died; these results were published in several scientific articles. After these findings, the chief aim was to go deeper regarding melatonin effects on apoptosis, focusing on a pathway called FoxO, linked to proteins of the same name. They refer to transcription factors, that is, proteins able to get into cell nucleus and induce the expression of other specific proteins.

“We have found that when human liver tumor cells are given melatonin, cell death increases specifically due to the fact that FoxO3a pathway is able to enter cell nucleus and induce Bim’s expression, a protein inducing cell death.”, he states.

Regarding the experiment control, the same melatonin doses were given to normal human liver cells and they found the effect on them is different, since it does not induce their death. Consequently, melatonin can be “an interesting substance, at least as an adjunct treatment, that is, as a complement of other therapies for hepatocellular carcinoma”, as José Luis Mauriz told us.

Notwithstanding, it is still at the preliminary study stage. “In order to bring this therapy to patients, we must deeply study FoxO pathways in tumor cells, then move to animals and eventually conduct studies on humans”, he warns.

Another finding in this in Vitro study on tumor cells is that patients with the worst prognosis “have the most inactive FoxO, functioning at lower levels”. “We have found melatonin induces FoxO’s mechanism; that is the reason why we believe these results are of special interest for these patients.”, he adds.

In Cooperation with the Universität Mainz

The research team, led by José Luis Mauriz, works with Javier González Gallego, Ibiomed director-general, on digestive and liver pathologies. Additionally, they belong to the Centro de Investigación Biomédica en Red (Networked Biomedical Research Center) de Enfermedades Hepáticas y Digestivas (Hepatic and Digestive Diseases), CIBERehd.

In this study, researchers have collaborated with the Universität Mainz, specifically with de Departments of Internal Medicine and Transplantation and Hepatobiliary Surgery, an international benchmark institution. One of the researchers, Sara Carbajo Pescador, stayed in this German university for three months to finish the research work carried out in León, Spain.

	References
	Carbajo-Pescador S., Steinmetz C., Kashyap A., Lorenz S., Mauriz JL., Heise M., Galle PR., González-Gallego J., and S Strand 2013 “Melatonin induces transcriptional regulation of Bim by FoxO3a in HepG2 cells”. British Journal of Cancer doi: 10.1038/bjc.2012.563