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Making Sense out of Antisense Thymidylate Synthase
Editorial Edward Chu, MD Chief, Section of Medical Oncology Professor of Medicine and Pharmacology Associate Director of Clinical Research, Yale Cancer Center Yale University School of Medicine New Haven, CT
Making Sense out of Antisense Thymidylate Synthase In this issue of Clinical Colorectal Cancer, Dr. Bruce Dolnick presents a succinct and timely review on the potential biologic role of a naturally occurring antisense thymidylate synthase (TS). It has been well established that the TScatalyzed reaction provides for the sole intracellular de novo source of thymidylate, which is an essential nucleotide precursor for DNA biosynthesis. For this reason, TS was initially identified as a potential target for cancer chemotherapy, and for more than 45 years, significant efforts have focused on identifying novel small-molecule TS inhibitors. Dolnick and his research group made the seminal discovery of a novel gene that codes for a naturally occurring antisense RNA complementary to TS messenger RNA (mRNA).1 The rTS gene overlaps the 3'-end of the TS mRNA, and it encodes 2 different protein products that are translated from alternatively spliced mRNAs, rTSα and rTSβ. Their initial studies suggested a direct interaction between the expression of these antisense TS proteins and TS expression and/or function. Dolnick et al demonstrated that the increased expression of rTSβ was directly associated with a reduced expression of TS.1,2 However, what was most intriguing was that the biologic effect of rTSβ was mediated by the formation of novel, methionine-derived signal molecules. These small molecules were found to be lipophilic in nature, and careful structural analysis revealed that they are similar to acyl-
12 • Clinical Colorectal Cancer May 2005
homoserine lactones in structure.3,4 Further work is presently ongoing in the Dolnick laboratory to characterize the precise structure of these methionine-derived small molecules as well as to begin to synthesize analogue compounds that could be used to inhibit TS expression. This work is important because it highlights the potential role of this methionine-signaling pathway as a novel regulatory mechanism for controlling TS expression. Moreover, these molecular-based studies pave the way for the rational design and development of completely novel small molecules that can be translated into the clinic for the treatment of colorectal cancer and other human malignancies.
Edward Chu, MD Editor-in-Chief
1. Black AR, Dolnick BJ. Expression of rTS corerelates with altered growth regulation of thymidylate synthase. Cancer Res 1996; 56:700-705. 2. Dolnick BJ, Lu K, Yin MB, et al. Recent advances in the study of rTS proteins: rTS expression during growth and in response to thymidylate synthase inhibitors in human tumor cells. Adv Enzyme Res 1997; 47:95-109. 3. Dolnick BJ, Angelino NJ, Dolnick R, et al. A novel function for the rTS gene. Cancer Biol Ther 2003; 2:364-369. 4. Dolnick BJ, Angelino NJ, Dolnick R, et al. Modulation of cell cycle genes and tumor cell growth by acyl-homoserine lactones. Proc Am Assoc Cancer Res 2003; 44:329 (Abstract #1454).
Making Sense out of Antisense Thymidylate Synthase In this issue of Clinical Colorectal Cancer, Dr. Bruce Dolnick presents a succinct and timely review on the potential biologic role of a naturally occurring antisense thymidylate synthase (TS). It has been well established that the TScatalyzed reaction provides for the sole intracellular de novo source of thymidylate, which is an essential nucleotide precursor for DNA biosynthesis. For this reason, TS was initially identified as a potential target for cancer chemotherapy, and for more than 45 years, significant efforts have focused on identifying novel small-molecule TS inhibitors. Dolnick and his research group made the seminal discovery of a novel gene that codes for a naturally occurring antisense RNA complementary to TS messenger RNA (mRNA).1 The rTS gene overlaps the 3'-end of the TS mRNA, and it encodes 2 different protein products that are translated from alternatively spliced mRNAs, rTSα and rTSβ. Their initial studies suggested a direct interaction between the expression of these antisense TS proteins and TS expression and/or function. Dolnick et al demonstrated that the increased expression of rTSβ was directly associated with a reduced expression of TS.1,2 However, what was most intriguing was that the biologic effect of rTSβ was mediated by the formation of novel, methionine-derived signal molecules. These small molecules were found to be lipophilic in nature, and careful structural analysis revealed that they are similar to acyl-
12 • Clinical Colorectal Cancer May 2005
homoserine lactones in structure.3,4 Further work is presently ongoing in the Dolnick laboratory to characterize the precise structure of these methionine-derived small molecules as well as to begin to synthesize analogue compounds that could be used to inhibit TS expression. This work is important because it highlights the potential role of this methionine-signaling pathway as a novel regulatory mechanism for controlling TS expression. Moreover, these molecular-based studies pave the way for the rational design and development of completely novel small molecules that can be translated into the clinic for the treatment of colorectal cancer and other human malignancies.
Edward Chu, MD Editor-in-Chief
1. Black AR, Dolnick BJ. Expression of rTS corerelates with altered growth regulation of thymidylate synthase. Cancer Res 1996; 56:700-705. 2. Dolnick BJ, Lu K, Yin MB, et al. Recent advances in the study of rTS proteins: rTS expression during growth and in response to thymidylate synthase inhibitors in human tumor cells. Adv Enzyme Res 1997; 47:95-109. 3. Dolnick BJ, Angelino NJ, Dolnick R, et al. A novel function for the rTS gene. Cancer Biol Ther 2003; 2:364-369. 4. Dolnick BJ, Angelino NJ, Dolnick R, et al. Modulation of cell cycle genes and tumor cell growth by acyl-homoserine lactones. Proc Am Assoc Cancer Res 2003; 44:329 (Abstract #1454).