Uncovering the mechanisms of a protein activator involved in promoting colorectal cancer, scientists from Rutgers Cancer Institute of New Jersey demonstrated that a small GTPase enzyme, known as Rab1A, is a key switch for amino acid signaling - a process that investigators say could play an important role in the development of malignancies and targeted cancer therapy.
The research involves mTORC1 protein complex, which is a central controller of cell growth and metabolism. Amino acids are not only essential nutrients, but also powerful chemical substances within the body that send a signal to turn on mTORC1-driven cell growth engine. Upon sensing the presence of amino acids, Rab1A GTPase enzyme becomes active, and stimulates another GTPase enzyme called Rheb to activate mTORC1 on the Golgi apparatus, which is previously known for transporting proteins within cells.
In the study, published in the current online edition of Cancer Cell, senior author X.F. Steven Zheng, PhD, co-leader of the Cancer Pharmacology and Preclinical Therapeutics Program at the Cancer Institute of New Jersey, and colleagues show that the Rab1A enzyme is often over produced in human cancers - especially colorectal cancer - and heightens the ability of amino acids to promote cell growth and metabolism through mTORC1. Although amino acid signaling is recently recognized as a key process for normal physiology, its importance in human diseases remains not well understood. The current study provides first evidence that aberrant elevation of amino acid signaling is a common cancer-driving phenomenon. Because tumors with overproduced Rab1A enzyme develop faster, and are more invasive and lethal, the level of Rab1A enzymes may be useful to facilitate clinical diagnosis.
Investigators also demonstrated that removal of the Rab1A enzyme selectively blocks cancer growth in those cells with excessive Rab1A enzyme. They further learned that a large presence of Rab1A leads to sensitivity of cancer cells toward the drug rapamycin, which blocks the growth-stimulating effect of mTORC1. As Dr. Zheng notes, this suggests that Rab1A can be considered a surrogate biomarker to predict the outcome of mTORC1-targeted cancer therapy. "In further elucidating the role Rab1A plays in amplifying amino acid signaling, we can further understand this impact on the mTORC1 protein. Especially since elevated levels of mTORC1 signaling is found in colorectal cancer, new therapy options targeted toward mTORC1 can be explored," notes Zheng, who is also a university professor of pharmacology at Rutgers Robert Wood Johnson Medical School.
Along with Zheng, the author team consists of Janice Thomas, Cancer Institute and Robert Wood Johnson Medical School; Yanjie Zhang, Cancer Institute and Shanghai Jiaotong University; Laura Morris, Cancer Institute and Graduate Program in Molecular and Cellular Pharmacology at Rutgers University; and Hui-Yun Wang, Robert Wood Johnson Medical School and Sun Yat-sen University.
The study was supported by grants from the National Cancer Institute (R01 CA173519 and R01 CA123391).