A team of researchers from Case Western Reserve School of Medicine has discovered how the cancer-related protein Bcl-2 signals cancer cells to live longer. The breakthrough emerged when the scientists discovered that Bcl-2 alters the level of calcium ions in lymphoma and leukemia cells that are resistant to cancer treatments. Published in the journal Proceedings of the National Academy of Sciences (PNAS), the research findings could help lead to the development of drugs that attack Bcl-2 in malignancies and produce better outcomes for cancer treatment.
"One of the deadliest and most remarkable characteristics of cancer cells is that regardless of where they are growing, and no matter what types of treatments are employed, including many different forms of chemotherapy and radiation therapy, the cancer cells have the ability to survive," said Clark W. Distelhorst, MD, Professor, Medicine-Hematology/Oncology, Pharmacology, Case Western Reserve School of Medicine.
"Since 1993 our team has been conducting research on key mechanisms by which the protein Bcl-2 keeps cancer cells alive."
"Our recent publication in the journal PNAS describes how Bcl-2 regulates calcium ions that carry information within cancer cells and promotes the survival of those cancer cells," said Distelhorst. "Now, for the first time, we have evidence of how Bcl-2 is promoting abnormally long survival of the cancer cells by regulating calcium levels within cells, and will use the discovery and data to deliver therapies designed to attack the Bcl-2 protein and inhibit its impact," said Distelhorst.
"We have recognized for decades that cancer cells grow and forget to die," said Stanton Gerson, MD, director of the Case Comprehensive Cancer Center and director of the Seidman Cancer Center at UH Case Medical Center. "For the first time now we understand why. Dr. Distelhorst's discovery is a breakthrough that will lead to new treatments for cancer. I predict that this work will focus the discovery of new drugs against the Bcl-2 calcium flow system," said Gerson.
More than a decade ago, the Distelhorst lab discovered that Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (IP3R) channel and regulates the release of calcium ions. In their most recent study, this team found that when Bcl-2 binds to the IP3R channel, it initiates a complex feedback mechanism that blocks the release of calcium ions intended to induce cell death. Instead of dying, the cancer cells continue to proliferate – even in the face of chemotherapy and radiation.
The research, led by hematology and oncology expert Clark W. Distelhorst, sheds new light on how Bcl-2 functions and the pathway it uses to prevent the death of cancer cells.
Bcl-2 can prolong the survival of cancer cells by limiting the release of calcium ions from the endoplasmic reticulum (transport system) of the cell. Elevations in intracellular calcium signal key events in the lifetime of a cell. These calcium ions encode information that governs many cellular processes - including cell division, cell proliferation, and even cell death – and travel via a specialized channel known as the IP3R.
Bcl-2's role in thwarting cancer treatment is best seem in lymphoid malignancies like chronic lymphocytic leukemia and lymphoma as well as in small cell lung cancer and other cancers characterized by high levels of Bcl-2. The Distelhorst lab used biochemical and cell physiological studies, molecular studies, and intracellular imaging to document major changes in the calcium content of the cells they studied.
The study appeared in the electronic edition of the Proceedings of the National Academy of Sciences (PNAS) on January 7, 2014.
This research was supported by NIH grants R01 CA085804 (CWD), R25 CA148052 (MC), 5T32HL007147 (AL) and 5T32GM007250 (AL).
About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.
Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."
The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu
About Case Comprehensive Cancer Center Case Comprehensive Cancer Center is an NCI-designated Comprehensive Cancer Center located at Case Western Reserve University. The center, now in its 25th year of funding, integrates the cancer research activities of the largest biomedical research and health care institutions in Ohio – Case Western Reserve, University Hospitals (UH) Case Medical Center and the Cleveland Clinic. NCI-designated cancer centers are characterized by scientific excellence and the capability to integrate a diversity of research approaches to focus on the problem of cancer. It is led by Stanton Gerson, MD, Asa and Patricia Shiverick- Jane Shiverick (Tripp) Professor of Hematological Oncology, director of the National Center for Regenerative Medicine, Case Western Reserve, and director of the Seidman Cancer Center at UH Case Medical Center.
Proceedings of the National Academy of Sciences