Sanford-Burnham researchers and their collaborators uncovered a new mechanism that may lead to unique treatments for lung cancer, one of the leading causes of death worldwide.
In the study, published May 15 in the journal Genes & Development, the team discovered that a protein called Bax Inhibitor-1 (BI-1) protects lung cancer cells and promotes tumor growth by regulating autophagy, a mechanism by which cells break down their own components and recycle the parts. Autophagy, which literally means “to eat oneself,” is essential to cell survival, particularly when food is scarce.
“Cancer cells are remarkably adaptive and depend on a variety of mechanisms to ensure their survival and continued growth when challenged by their environment,” says John C. Reed, M.D., Ph.D., Sanford-Burnham’s CEO and senior author of the study. “By reducing levels of BI-1, it appears we were able to modulate intracellular signals and starve lung cancer cells of the energy needed to carry out one of their most important survival mechanisms—autophagy.”
The researchers showed that BI-1 appeared to be linked to levels of calcium, which aids in cellular communication. Suppressing BI-1 reduced calcium levels in the endoplasmic reticulum, the interconnected network of sacs and tubules that manufacture, process, and transport a variety of compounds for use inside and outside of cells. Lowering BI-1 levels led to reduced mitochondrial activity, oxygen consumption, and adenosine triphosphate (ATP) levels. ATP is often called the “molecular unit of currency” due to the important role it plays in transporting chemical energy needed for metabolism.
These findings were confirmed by animal models that showed BI-1 suppression reduced human lung cancer tumor growth.
“These studies are the first to show that BI-1 may play an important survival role in cells under circumstances where oxygen and nutrient deprivation are encountered, such as the conditions that arise in advanced tumors or when cells are stressed by chemotherapy treatments,” says co-author Paul B. Fisher, M.Ph., Ph.D., of Virginia Commonwealth (VCU) Massey Cancer Center. “We are excited by our findings because they uncover a new pathway that may be an effective target for future therapies to treat advanced lung cancer.”
Next, the researchers hope to apply their findings to screen for potential drugs that can reduce BI-1-mediated protective autophagy in cancer cells.
Reed and Fisher collaborated with lead author Renata Sano, Ph.D. from Sanford-Burnham, Michael Hedvat, Ph.D., a VCU and Sanford-Burnham postdoctoral scholar working in Reed’s laboratory, Shu-Ichi Matsuzawa, Ph.D., Russell Dahl, Ph.D., Ying-Chen Claire Hou, Ph.D., Ricardo G. Correa, Ph.D., Chih-Wen Shu, Ph.D., Maryla Krajewska, M.D., and Paul W. Diaz, Ph.D., from Sanford-Burnham; Giovanni Quarato, Ph.D., and Roberta A. Gottlieb, M.D., from San Diego State University; Masaya Yamaguchi, Ph.D., and Victor Nizet, M.D., from the University of California, San Diego; David D. Thomas, Ph.D., from University of Minnesota; and Stephen W. Tait, Ph.D., and Douglas R. Green, Ph.D., from St. Jude Children’s Hospital.
This study was supported by NIH grant AG-15393, the Tobacco-Related Disease Research Foundation, and an inter-institutional agreement between Sanford-Burnham Medical Research Institute and VCU School of Medicine through a visiting professorship at Sanford-Burnham held by Fisher, and support provided to Dr. Hedvat. It was also supported, in part, with funding from VCU Massey Cancer Center’s NIH-NCI Cancer Center Support Grant P30 CA016059.
Sano R, Hou YC, Hedvat M, Correa RG, Shu CW, Krajewska M, Diaz PW, Tamble CM, Quarato G, Gottlieb RA, Yamaguchi M, Nizet V, Dahl R, Thomas DD, Tait SW, Green DR, Fisher PB, Matsuzawa S, & Reed JC (2012). Endoplasmic reticulum protein BI-1 regulates Ca2+-mediated bioenergetics to promote autophagy. Genes & development, 26 (10), 1041-54 PMID: 22588718