Exterminating protein

A team of Brazilian scientists discovered the molecular mechanism that controls expression of tumor necrosis factor-related apoptosis-inducing ligand in chronic mylegenous leukemia

By Fábio de Castro

Agência FAPESP – A protein discovered in 1995 capable of annihilating tumor cells while leaving healthy cells intact, is considered one of the body’s most powerful natural resources to deter cancer. Nevertheless, in certain types of cancer the expression of this protein, known as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), is inhibited, which allows tumors to evolve normally. 

A team of Brazilian scientists discovered the molecular mechanism that controls expression of TRAIL in chronic mylegenous leukemia (CML). The study, which shows how the “anti-cancer trap” is disarmed, paves the way for broader investigation into alternative therapeutic treatments for the disease.

The study, published in the Nature group’s magazine Oncogene, was coordinated by Gustavo Amarante-Mendes, professor at the Immunology Department of the Biomedical Sciences Institute (ICB) at Universidade de São Paulo (USP) and researcher at the National Science and Technology Institute’s Immunological Investigation Institute (iii-NCT).

The scientist is currently coordinating a research project, financed by FAPESP under its Regular Research Grants program. The project is focused on ICB-USP’s area of expertise: studies on molecular mechanisms that regulate cellular necrosis in cancer and immune system cells.

According to Amarante-Mendes, the study became the research topic for the doctoral thesis penned by Daniel Diniz de Carvalho, author of the article. Welbert de Oliveira Pereira and Janine Leroy, doctoral and master’s students, respectively, also collaborated. The three were FAPESP fellows.

Throughout the project’s development (beginning in 2007), the study has received several awards, including Nature Reviews Cancer Award during the 8th São Paulo Research Conference, second place in the Michel Jamra Award for Young Researchers during the 23rd Annual Meeting of the Federation of Experimental Biology Societies (FeSBE), in addition to receiving the  Ricardo Pasquini Award for best study on chronic mylegenous leukemia (CML) presented at the congress of the Brazilian Hematology and Hemotherapy Association
(Hemo 2009).    

According to Amarante-Mendes, the TRAIL protein induces target-cells to necrosis by initiating a complex and well regulated molecular program known as apoptosis, which is activated during embryonic development to form organs and tissue. In adult life, apoptosis--or programmed cellular death – plays a fundamental role in the renewal of cells.

“Defects in the process of apoptosis are observed in the diverse forms of cancer and the acquisition of resistance to apoptosis is considered one of the stages in the genesis process of tumors. Some forms of cancer are capable of developing resistance to the necrosis induced by TRAIL. Others, like LMC, inhibit TRAIL production, sidestepping this important defense mechanism. Our study has demonstrated how this molecular mechanism works,” comments Amarante-Mendes to Agência FAPESP.

According to the scientist, CML is caused by a chimeric protein – that is, which should not normally exist in the organism – and that emerges as a result of “confusion” between the chromosomes 9 and 22, which splice together.

“It is what we call chromosomal translocation: the ABL protein of chromosome 9 is transferred to the BCR region of chromosome 22. This generates an atypical chromosome, the so-called Philadelphia chromosome, which is associated with CML. Our study investigates the molecular mechanism responsible for inhibition of TRAIL expression in BCR-ABL positive leukemic cells,” he explains.  The study, according to Amarante-Mendes, involved the collaboration of other research groups, including teams coordinated by Marco Antonio Zago, provost of research at USP, Eliana Abdelhay, of the National Cancer Institute (Inca), and professors Fabíola Castro (at the Pharmaceutical Sciences School of USP’s Ribeirão Preto campus -  FCF-RP-USP) and Jacqueline Jacysyn (at USP’s Medical School – FMUSP).

Magic Bullet

Initially, the team observed that TRAIL expression diminished significantly as CML progresses and that this decrease was directly related to increased expression of another protein: PRAME (preferentially expressed antigen in melanoma).

“PRAME is usually not found in normal cells, but is frequently found in tumor cells. After determining this, we observed that PRAME is directly responsible for inhibiting TRAIL expression in leukemic cells,” says Amarante-Mendes.

According to him, PRAME is responsible for recruiting proteins capable of inhibiting genetic transcription through epigenetic mechanisms. “The study showed that this mechanism also has therapeutic implications for CML, since PRAME inhibition through RNA interference is capable of generating greater TRAIL expression, making leukemic cells more susceptible to apoptosis, and consequently, to the therapy,” he affirms.
When TRAIL was discovered back in 1995, the protein was considered the magic bullet for the future of cancer treatment because it killed the cellular strains in tumor cultures, while simultaneously preserving the primary strains. Accordingly, some clinical treatments based on TRAIL have been developed.

“The problem is that some forms of cancer are resistant to this signal.  In other forms, like the case studied, the BCR-ABL gene lowers TRAIL expression. This is why we focused our studies on the task of uncovering this mechanism,” notes Amarante-Mendes.
 
It is possible that the same mechanism discovered by researchers, according to him, could occur not only in CML, but in other types of tumors where PRAME expression is elevated. “This possibility – and its clinical implications – is the next step for our studies,” says the scientist. The topic, according to him, is already being investigated by Bárbara Mello, who is developing her doctoral studies at ICB’s laboratory with a grant from FAPESP.

The article BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients (doi:10.1038/onc.2010.409) by Gustavo Amarante-Mendes, can be read by subscriber of Oncogene in www.nature.com/onc/journal/v30/n2/abs/onc2010409a.html.