hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing

Rachel Wilson Goehe ¹, Jacqueline C Shultz , Charuta Murudkar

⁰Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.

The Journal of Clinical Investigation +

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October 26, 2010

View abstract on PubMed

Summary

Dysregulated caspase-9 splicing in non-small cell lung cancer (NSCLC) is linked to altered hnRNP L activity. This study reveals a cancer-specific hnRNP L phosphorylation mechanism essential for NSCLC tumor growth.

Area Of Science

Molecular Biology
Cancer Research
Apoptosis

Background

Caspase-9 is integral to the intrinsic apoptotic pathway and acts as a tumor suppressor.
The expression of caspase-9 is governed by post-transcriptional pre-mRNA processing, yielding pro-apoptotic (caspase-9a) and anti-apoptotic (caspase-9b) splice variants.

Purpose Of The Study

To investigate the mechanisms regulating caspase-9 splice variant ratios in non-small cell lung cancer (NSCLC).
To identify the role of heterogeneous nuclear ribonucleoprotein L (hnRNP L) in caspase-9 pre-mRNA processing and its impact on NSCLC tumorigenesis.

Main Methods

Analysis of caspase-9 splice variant ratios in NSCLC tumors.
Mechanistic studies involving exonic splicing silencer (ESS) and hnRNP L interaction.
Investigation of hnRNP L expression and its effect on splice variant ratios in NSCLC and non-transformed cells.
Identification of post-translational modifications, specifically phosphorylation at Ser52.
Validation in a mouse xenograft model.

Main Results

The ratio of caspase-9 splice variants is dysregulated in NSCLC tumors.
hnRNP L interacts with an ESS to regulate caspase-9 pre-mRNA processing.
Downregulation of hnRNP L increases the caspase-9a/9b ratio in NSCLC cells.
hnRNP L phosphorylation at Ser52 is critical for regulating the caspase-9a/9b ratio in a cancer-specific manner.
Reduced hnRNP L expression leads to loss of tumorigenic capacity in NSCLC cells.

Conclusions

A novel cancer-specific mechanism involving hnRNP L phosphorylation regulates caspase-9 splice variant ratios.
This mechanism, by lowering the caspase-9a/9b ratio, is crucial for maintaining the tumorigenic potential of NSCLC cells.
Targeting hnRNP L or its regulatory pathway may offer therapeutic strategies for NSCLC.

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