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Suppression of FOXO1a gene might kill resistant ARMS tumors


FOXO1a caused death of tumor cells in laboratory study by triggering expression of caspase-3, which blocks cell division and causes cells to undergo apoptosis, according to St. Jude.

The loss of function of a gene called FOXO1a plays an important role in the development of the most common cancer of soft tissues in children, and restoring the function of that gene in cancer cells suppresses that cancer, according to investigators at St. Jude Children’s Research Hospital. The cancer, called alveolar rhabdomyosarcoma (ARMS), arises from immature skeletal muscle cells that remain partially differentiated (do not acquire all the characteristics of a mature muscle cell).

The St. Jude team found that the expression of FOXO1a is suppressed in ARMS and that the gene potently suppresses tumor activity when re-introduced into ARMS tumor cells in the laboratory. Therefore, the investigators theorize that the observed loss of FOXO1a activity is a pivotal step in the ARMS development. The FOXO1a gene produces the protein FOXO1a. Gene expression refers to the production of the protein coded for by a particular gene. A report on these findings appears in the September 12 issue of Journal of Cell Biology.

FOXO1a kills ARMS cells by activating the gene that produces a protein called caspase-3. Caspase-3 is a key player in the signaling pathway that triggers programmed cell death (apoptosis). Although caspase-3 triggers apoptosis in abnormal cells, normal myoblasts (immature muscle cells) also depend on caspase-3 activity in order to differentiate into mature muscle cells.

"Our study shows that suppression of FOXO1a is necessary for ARMS cells to survive and avoid caspase-3-mediated apoptosis, even in the more aggressive secondary tumors that are highly resistant to irradiation and chemotherapy, said Gerard Grosveld, Ph.D., chair of genetics and tumor cell biology at St. Jude. Grosveld is senior author of the paper. His team previously reported that FOXO1a (also called FKHR) is the master regulator that controls the differentiation of myoblasts into muscle cells (EMBO Journal 22:1147-1157; 2003).

The investigators also showed that the loss of FOXO1a expression works in combination with another mutation in ARMS. Specifically, muscle cells first acquire a mutation called a chromosomal translocation. Translocation occurs when two chromosomes break and exchange the pieces of DNA that break off. Because the chromosome breaks occur within genes, a piece of a gene from one chromosome is able to combine with the remaining piece of gene on the other chromosome. When two broken normal genes combine, the outcome is an abnormal gene called a fusion gene. In ARMS, the two possible fusion genes that arise by translocation are called PAX3-FOXO1a and PAX7-FOXO1a. Translocation destroys one of the two copies of FOXO1a, Grosveld noted.

If the remaining FOXO1a gene then fails to produce FOXO1a protein, the combination of the absence of FOXO1a with the gene translocation causes ARMS.

The finding suggests that drugs aimed at restoring or increasing the activity of FOXO1a in ARMS might successfully treat this cancer in children by forcing the abnormal cells to undergo apoptosis. Furthermore, the mutations that cause ARMS do not occur in the related but different muscle cancer ERMS (embryonal rhabdomyosarcoma), the researchers reported. Therefore, forcing the expression of FOXO1a in these cancer cells does not cause them to undergo apoptosis.

The proteins made by the PAX3 and PAX7 genes play critical roles in the development and differentiation of muscle cells, and the translocations disrupt their important functions, according to Grosveld. "So it’s not surprising that ARMS cells look like skeletal muscle cells that only partially differentiated," Grosveld said. "And in the absence of FOXO1a protein, these abnormal cells simply continue to grow and multiply and cause ARMS."

"Our findings emphasize that ARMS and ERMS are different forms of rhabdomyosarcoma that arise by independent mutations," said Philppe R. J. Bois, Ph.D., the postdoctoral fellow who did most of this work. "Therefore, different strategies will be required to improve treatment outcomes for each of these tumors." Bois is first author of the paper.

Other authors of this paper include Kamel Izeradjene, Peter J. Houghton, John L. Cleveland and Janet A. Houghton.

Kelly Perry | EurekAlert!
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