Skewed Caspase-9 Expression Drives Tumorigenicity of Lung Cancer Cells

The ability of non-small-cell lung cancer (NSCLC) cells to form tumors and spread is controlled by variations in RNA expression that determine the ratio of pro- and anti-apoptotic forms of the enzyme caspase-9.

Caspase-9 is involved in the intrinsic apoptotic pathway, and it has been implicated as playing a role as a tumor suppressor. However, so far little is known about the mechanisms governing caspase-9 expression.

Investigators at Virginia Commonwealth University (Richmond, USA) worked with a model system in which human NSCLC cells were transplanted into mice. They manipulated this model by using virus-based targeted gene therapy to reduce the amount of heterogeneous nuclear ribonuclear protein family member L (hnRNP L) in the NSCLC cells. HnRNP L is a member of the hnRNP family of RNA processing factors and regulates the expression of two caspase-9 variants, the proapoptotic caspase-a and the antiapoptotic caspase-b, through a process known as RNA splicing.

Results published in the October 25, 2010, online edition of the Journal of Clinical Investigation revealed that the ratio of caspase-9a to caspase-9b differed markedly between normal lung cells and NSCLC cells. Increased caspase-9b in NSCLC cells acted to promote tumor formation, growth, and maintenance. Gene therapy that caused the downregulation of hnRNP L in NSCLC cells induced a complete loss of tumorigenic capacity that was due to the changes in caspase-9 introduced prior to RNA processing. This effect was demonstrated at the molecular level by the finding that hnRNP was specifically phosphorylated in NSCLC. The phosphorylated hnRNP L, in turn, promoted expression the antiapoptotic caspase-9b, thereby contributing to tumorigenesis.

"We are researching an unexplored area of RNA splicing factors in relation to cancer,” said senior author Dr. Charles E. Chalfant, associate professor of biochemistry and molecular biology at Virginia Commonwealth University. "Before this study, there had been very little evidence of an RNA splicing event that results in cancerous tumor development. This study points to caspase-9b as being a very important target in the development of a durable therapy for non-small-cell lung cancer.”

"Unfortunately, many current therapies for lung cancer are less effective and more toxic than we would like,” said Dr. Chalfant. "Lung cancer kills more people than any other cancer, and there is a real need for new cellular targets that are cancer-specific and show results in large numbers of patients regardless of the mutations found in individual tumors. Since caspase-9b is mainly expressed in malignant cells, these findings may provide innovative treatments for non-small-cell lung cancer with little to no toxic side effects.”

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