Researchers at Purdue University have discovered a molecular mechanism that may play a crucial role in cancer's ability to resist chemotherapy and radiation treatment and that also may be involved in Alzheimer's and heart disease.
The scientists, using an innovative imaging technique invented at Purdue, have learned that a protein previously believed to be confined to the nucleus of healthy cells actually shuttles between the nucleus and cytoplasm, the region of the cell surrounding the nucleus. Moreover, the protein's shuttling is controlled by the presence of another protein in the nucleus and its attachment to that second protein.
"Our findings may provide a new avenue for the development of innovative treatments for certain cancers and other conditions," said Chang-Deng Hu, an assistant professor in Purdue's Department of Medicinal Chemistry and Molecular Pharmacology and an investigator at the Walther Cancer Institute in Indianapolis.
The experiments were done using a line of "teratocarcinoma" malignant tumor cells from mice called F9, which, when subjected to the right biochemical signals, have the ability to alter their properties and are considered to be "cancer stem cells." The hypothetical cancer-resistance role of cancer stem cells could explain why tumors return after treatment. If stem cells prove to be critical to cancer's resistance to treatment, new medications might be developed to target cancer stem cells while chemotherapy or radiation is administered, Hu said.
Research findings are detailed in a paper appearing this month in the EMBO Journal, published by the European Molecular Biology Organization. The paper was written by postdoctoral research associate Han Liu, laboratory technician Xuehong Deng and graduate student Y. John Shyu, all in the Department of Medicinal Chemistry and Molecular Pharmacology; Jian Jian Li, an associate professor in the Department of Health Sciences; Elizabeth J. Taparowsky, a professor in the Department of Biological Sciences; and Hu.
The research focuses on two proteins called c-Jun and ATF2, which are key components of a protein complex called activating protein-1, or AP-1. AP-1 is a major "transcription factor" that binds to DNA, activating the "expression" of genes required to produce proteins needed for vital cellular processes. The proteins that make up AP-1, including ATF2 and c-Jun, often join together in the nucleus, forming either "homodimers," when two of the same proteins join, or "heterodimers," when two different proteins come together.
"Current thinking is that all of these AP-1 proteins in healthy cells are localized, or confined, to the nucleus," Hu said. "But in this work we found for the first time that ATF2 constantly shuttles between the cytoplasm and the nucleus."
The researchers found that the ATF2 protein possesses "nuclear export" and "nuclear localization" signals, which enable it to travel out of and back into the nucleus, respectively. The researchers also discovered that if ATF2 attaches to c-Jun in the nucleus, forming a heterodimer, the nuclear export signal is blocked, preventing ATF2 from traveling from the nucleus to the cytoplasm.
Researchers had already known that chemotherapy and radiation cause cancer cells to increase production of ATF2. The Purdue researchers found that "overexpressed," or overproduced, ATF2 is predominantly located in the cytoplasm because of an inadequate amount of c-Jun in the nucleus, suggesting it is likely that overexpressed ATF2 also may be localized in the cytoplasm in cancer cells, Hu said.