Understanding h-prune biology in the fight against cancer

Abstract

The h-prune protein is a member of the DHH protein superfamily, and its overexpression in breast, colorectal and gastric cancers correlates with depth of invasion and degree of lymph-node metastasis. Taken together with the observation that h-prune is highly expressed in metastatic breast cancer, this suggests that h-prune can be used as a marker for the identification of subsets of cancer patients with highly aggressive tumours. H-prune possesses a phosphodiesterase (cAMP-PDE) activity, and inhibition of PDE activity with dipyridamole suppresses cell motility. H-prune interacts with nm23-H1, GSK-3beta and gelsolin. Although a correlation between an h-prune PDE activity and cellular motility has been shown, GSK-3beta does not affect the PDE activity of h-prune. Inhibition of the interactions between h-prune and GSK-3beta and nm23-H1 additively suppresses the migration of colon cancer and breast cancer cells, thus suggesting that h-prune regulates cell motility by two different means of action: through its PDE activity and in its interactions with protein partners. Therefore, the identification of highly specific inhibitors of h-prune should be useful in the development of drugs to treat cancer metastasis.

The metallophosphodiesterase Mpped2 impairs tumorigenesis in neuroblastoma

“…Additionally, this impairment of cAMP and/or cGMP generation by overexpression of PDE isoforms has been described in various cancer pathologies, e.g., overexpression of PDE11A and PDE8B (showing genetic predisposition to adrenocortical hyperplasia tumors 35,36 ) and of h-Prune, which is implicated in breast cancer metastasis and colon, pancreas, gastric and esophageal cancers. 36,37 In the present study, we demonstrate that Mpped2 reduces cell proliferation and anchorage-independent growth and induces apoptosis. Results are also confirmed in vivo using xenograft NB models.…”

Binding of estrogen receptor α/β heterodimers to chromatin in MCF-7 cells

“…Finally, the mRNA levels of NOTCH2 and PRUNE were unaffected by the presence of ERb. These genes are both implicated in the aggressiveness of breast neoplasm (Marino & Zollo 2007, Wang et al 2008. Considering that all selected genes exhibit significant ERa/b heterodimer recruitment, our data suggest that ERb may have an activating or inhibitory influence on ERa through heterodimerization.…”

ASAP1 promotes tumor cell motility and invasiveness, stimulates metastasis formation in vivo, and correlates with poor survival in colorectal cancer patients

“…Using co-immunoprecipitation, we also show here that ASAP1 interacts with h-prune, a protein known to promote metastasis (Marino and Zollo, 2007). Furthermore, ASAP1 stimulates the phosphodiesterase activity of h-prune, an activity required for its motility-promoting properties (D'Angelo et al, 2004).…”

“…Like ASAP1, h-prune directly interacts with cortactin (Zollo, unpublished). It also stimulates metastasis formation, and promotes cell motility through its phosphodiesterase activity (Marino and Zollo, 2007); h-prune also negatively regulates the metastasis suppressor protein nm23-H1 (D'Angelo et al, 2004) that interacts with Arf protein (Palacios et al, 2002). Given these observations, we reasoned that ASAP1 may interact with h-prune.…”