Nuclear PTHrP targeting regulates PTHrP secretion and enhances LoVo cell growth and survival

Parathyroid hormone-related protein (PTHrP) is expressed by human colon cancer tissue and cell lines; expression correlates with colon carcinoma severity. PTHrP is synthesized as a prepro isoform and contains two targeting sequences — a signal sequence and a nuclear localization signal (NLS). The si...

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Bibliographic Details
Published in:Regulatory peptides 2009-11, Vol.158 (1), p.149-155
Main Authors: Bhatia, V., Saini, M.K., Falzon, M.
Format: Article
Language:English
Subjects:
Anchorage independence
Apoptosis
Cell Division
Cell Line, Tumor
Cell Nucleus - metabolism
Cell Survival
Gene Silencing
Humans
LoVo (colon cancer cells)
Nuclear localization signal
Parathyroid hormone-related protein
Parathyroid Hormone-Related Protein - genetics
Parathyroid Hormone-Related Protein - metabolism
Parathyroid Hormone-Related Protein - secretion
Polymerase Chain Reaction
Signal peptide
Signal Transduction
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Summary:Parathyroid hormone-related protein (PTHrP) is expressed by human colon cancer tissue and cell lines; expression correlates with colon carcinoma severity. PTHrP is synthesized as a prepro isoform and contains two targeting sequences — a signal sequence and a nuclear localization signal (NLS). The signal peptide (SP) directs PTHrP to the secretory pathway, where it exerts autocrine/paracrine effects. The NLS directs PTHrP to the nucleus/nucleolus, where it exerts intracrine effects. In this study, we used the human colon cancer cell line LoVo as a model system to study the effects of autocrine/paracrine and intracrine PTHrP action on cell growth and survival, hallmarks of malignant tumor cells. We report that PTHrP increases cell growth and survival, protects cells from serum-starvation-induced apoptosis, and promotes anchorage-independent cell growth via an intracrine pathway. Conversely, autocrine/paracrine PTHrP action decreases cell growth and survival. We also show an inverse relationship between secreted and nuclear PTHrP levels, in that cells overexpressing NLS-deleted PTHrP secrete higher PTHrP levels than those overexpressing the wild-type isoform. Conversely, SP deletion results in higher nuclear PTHrP levels. These observations provide evidence of a link between intracrine PTHrP action and cell growth and survival. Targeting PTHrP production in colon cancer may thus prove therapeutically beneficial.
ISSN:0167-0115
1873-1686
DOI:10.1016/j.regpep.2009.07.008