In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 11 ( 2012-03-13)
Abstract:
Our work has established a member of the AARS family as a unique, natural defender against tumor growth and development, offering hope for new therapies against specific cancers. For example, 〉 30,000 new cases of renal cell carcinoma (RCC) are recorded in the United States each year. Evidence points to a role for components associated with GRS-dependent tumor suppression—namely, ERK signaling and CDH6—in RCC. ERK signaling has also been implicated in small cell lung carcinoma. In general, GRS-based therapies could act against cancers in which CDH6 is highly expressed and the ERK pathway is active. Having shown such a role in the cell setting, we next looked for such a role in vivo, examining the consequences of administering GRS to animals that had ERK-signaling–dependent tumors. For this experiment, we chose mice that had developed aggressive cancers. We injected GRS not into the tumor itself, but instead under the skin at a peripheral site. Here, GRS could ultimately enter the serum and reach the tumor through the circulatory system. We felt that this approach would most closely mimic the situation in which GRS in the serum acts as part of a natural defense. Strikingly, this GRS administration strongly suppressed the growth and spread of the tumor and, in fact, resulted in tumor regression. To offer further evidence for the role of GRS in suppressing ERK signaling and causing tumor cell death, we used antibodies to create an artificial shield around CDH6, blocking the ability of GRS to stick to tumor cells. As expected, this shield prevented GRS from inhibiting signaling from ERK. The result shows GRS's role as a natural defense against those tumor cells that require ERK signaling. In our experiments with whole cells in the laboratory, we found that GRS is secreted from macrophages—a type of immune cell that engulfs foreign invaders. Secretion is stimulated by a molecule—called Fas ligand—that is released from tumor cells. Thus, the tumor cell itself plays a role in GRS's appearance in the serum. These tumor cells become malignant, because they harbor a cancer-causing gene called the ras oncogene, which gives instructions for making the ras protein. The ras protein's ability to cause tumors depends on the action of another cell component called ERK. We found that, once released, GRS was able to stick to the surface of the Fas-secreting tumor cells through a cancer-specific partner named cadherin (CDH)6 (or K-cadherin). The union of GRS with CDH6 set off a cascade of events that, ultimately, inhibited signaling from ERK. Without signaling from ERK, growth and proliferation of the tumor cells was arrested, and cell death resulted ( Fig. P1 ). With these considerations in mind, we decided to investigate the functions of AARSs, starting with examples of these synthetases that are present in a physiological setting where no protein synthesis occurs. We looked more closely at those synthetases that circulate in human serum (a component of blood containing no blood cells or clotting factors). Curiously, ∼30% of all autoimmune patients, including those suffering from inflammatory and lung diseases, have autoantibodies directed against one of seven AARSs ( 3 , 4 ). In general, antibodies are immune molecules that usually attach to specific invaders. Autoantibodies are antibodies that attach to the organism's own molecules. Glycyl-tRNA synthetase (GRS) is one of the AARSs targeted by these autoantibodies. Particularly interesting was the observation that autoantibodies directed against GRS were also detected in the serum of patients with cancer ( 5 ). These results led us to investigate the possibility of a role for GRS in the cancer microenvironment. A group of 20 enzymes called aminoacyl-tRNA synthetases (AARSs) forms an essential component of all living cells, helping to translate information encrypted in genes. This “translation” is done during protein synthesis within the cell. Interestingly, over the last 12 y, researchers have discovered activities for these enzymes that are not associated with protein synthesis ( 2 , 3 ), including the regulation of inflammatory responses, the development of blood vessels, and diverse other functions. On the basis of these findings, we now believe that perturbations in these functions may help explain the connections between AARSs and many diseases. The causes of cancerous tumors and the mechanisms behind immune system responses to them have been extensively studied. Still, we have limited understanding of the complete arsenal of natural defense systems against tumors ( 1 ). In this study, we made the surprising observation that a conventional component of the body's protein-synthesis machinery, not thought to have a connection to tumor defense, in fact plays a role in the suppression of specific cancers. This function was demonstrated in laboratory experiments on cells and separately in vivo in animals that bore tumors. The results may form the basis for potential cancer therapeutics.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1200194109
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2012
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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