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Controversial Klotho in cancer

Posted Oct 14 2008 4:09am

The soluble protein Klotho was initially widely believed to be an anti-aging factor: knockout mice live short lives and display symptoms of segmental progeria, and increasing klotho gene dosage protects the kidneys against age-related decline. Mechanistic studies suggested that loss-of-function mutations in klothoderepress the Wnt signaling pathway, resulting in premature cellular senescence.

More recently, however, the relationship between Klotho and bona fide aging has been called into question — specifically by the claim that klotho mutants are suffering from hypervitaminosis D. While this syndrome can phenocopy some aspects of aging (so the argument goes) it does not represent premature aging as such: the klotho mutant phenotype can be partially rescued by placing mice on a diet low in vitamin D, a regimen that does nothing to slow normal aging. This has led some to argue that Klotho should no longer be considered a pro-longevity factor.

The tennis match continues, most recently with a forceful volley from the pro-” klotho as anti-aging gene” side of the court. Wolf et al. remind us that Klotho downregulates the IGF-I signaling pathway (in which loss-of-function mutation generally extends lifespan; this is consistent with a bona fide anti-aging role for Klotho), and describe the gene’s effects on the proliferation of breast cancer cell lines:

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

Klotho is an anti-aging gene, which has been shown to inhibit the insulin and insulin-like growth factor 1 (IGF-1) pathways in mice hepatocytes and myocytes. As IGF-1 and insulin regulate proliferation, survival and metastasis of breast cancer, we studied klotho expression and activities in human breast cancer. Immunohistochemistry analysis of klotho expression in breast tissue arrays revealed high klotho expression in normal breast samples, but very low expression in breast cancer. In cancer samples, high klotho expression was associated with smaller tumor size and reduced KI67 staining. Forced expression of klotho reduced proliferation of MCF-7 and MDA-MB-231 breast cancer cells, whereas klotho silencing in MCF-7 cells, which normally express klotho, enhanced proliferation. Moreover, forced expression of klotho in these cells, or treatment with soluble klotho, inhibited the activation of IGF-1 and insulin pathways, and induced upregulation of the transcription factor CCAAT/enhancer-binding protein beta, a breast cancer growth inhibitor that is negatively regulated by the IGF-1-AKT axis. Co-immunoprecipitation revealed an interaction between klotho and the IGF-1 receptor. Klotho is also a known modulator of the fibroblast growth factor (FGF) pathway, a pathway that inhibits proliferation of breast cancer cells. Studies in breast cancer cells revealed increased activation of the FGF pathway by basic FGF following klotho overexpression. Klotho did not affect activation of the epidermal growth factor pathway in breast cancer cells. These data suggest klotho as a potential tumor suppressor and identify it as an inhibitor of the IGF-1 pathway and activator of the FGF pathway in human breast cancer.

In summary, then: As in other systems, Klotho downregulates the IGF-1 pathway in breast cancer (from the co-IPs, it looks like it might be acting as a receptor antagonist). Systemic downregulation of the IGF-1 pathway results in lifespan extension; here, it appears to slow proliferation of two cultured breast cancer cell lines with rather different behavioral profiles (MB-231 is quite aggressive, whereas MCF-7 is more genteel). From the tissue arrays, the Klotho expression pattern behaves as one would expect for a tumor suppressor: high in normal breast tissue but low in tumor cells; within tumors, higher Klotho correlates with endpoints associated with better outcomes (smaller tumors and lower levels of proliferation markers).

Within the larger context of the Klotho controversy, this study is a staunch argument in favor of continued study of the gene as an anti-tumor and anti-aging factor: in this system at least, Klotho is slowing tumor growth and inactivating a gerontogene. ( Let us take as read the somewhat bitchy criticism that most of the main results are from cell culture, and that it would be nice to see confirmation in whole-organism studies.) Thus, the results deal a strong blow against the claim that the Klotho phenotypes are an epiphenomenon resulting from a derangement of vitamin metabolism. After all, one can’t cure cancer by withholding vitamin D.

      
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