Atorvastatin prevents ATP-driven invasiveness via P2X7 and EHBP1 signaling in PTEN-expressing prostate cancer cells

Abstract

Epidemiological studies indicate that statins, cholesterol-lowering drugs, prevent aggressive prostate cancer and other types of cancer. Employing essentially non-prostate cell lines, we previously showed that statins rapidly downregulate nuclear levels of phosphorylated Akt via P2X7, a purinergic receptor recently implicated in invasive growth. Here, we present studies on phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-positive prostatic cells. We document an involvement of EH domain-binding protein 1 (EHBP1), previously associated with aggressive prostate cancer and insulin-stimulated trafficking and cell migration, in P2X7 signaling. We also show that EHBP1 is essential for an anti-invasive effect of atorvastatin. Furthermore, EHBP1 interacted with P-Rex1, a guanine nucleotide exchange factor previously implicated in invasive growth. Mevalonate did not prevent this anti-invasive effect of atorvastatin. These data indicate that atorvastatin modulates invasiveness via P2X7, EHBP1 and P-Rex1. Interestingly, the interaction between EHBP1 and P-Rex1 was not induced by extracellular adenosine triphosphate (ATP), the endogenous P2X7 ligand, and statins counteracted invasiveness stimulated by extracellular ATP. In support of these experimental data, a population-based genetic analysis showed that a loss of function allele in the P2X7 gene (rs3751143) associated with non-aggressive cancer, and the common allele with aggressive cancer. Our data indicate a novel signaling pathway that inhibits invasiveness and that is druggable. Statins may reduce the risk of aggressive prostate cancer via P2X7 and by counteracting invasive effects of extracellular ATP.

Accelerated Tumor Progression in Mice Lacking the ATP Receptor P2X7

“…In tumor cells, P2X7R is constantly and tonically active, thus causing: (i) moderate increase in the endoplasmic reticulum and mitochondrial Ca 2þ concentration; (ii) enhanced efficiency of oxidative phosphorylation; (iii) increase in intracellular ATP stores; (iv) activation of the transcription factor NFATc1; (v) stimulation of aerobic glycolysis; and (vi) stimulation of proliferation (5,38,40,42,43).…”

Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells

“…PTEN is one of the key regulation factors in the process of DNA repair and the expression is then increased in order for it to participate in the process of cancer development (26,27). In previous studies, PTEN was tested in PCa and hyperplastic prostate tissues, and it was observed to be mainly expressed in PCa tissues and in the cell nuclei of hyperplastic prostate tissues (28,29). The expression of PTEN in PCa was significantly higher than that in prostate hyperplasia, which indicated that increased PTEN expression levels may be associated with the incidence of PCa (30,31).…”

Therapeutic Targeting of the Cancer-Specific Cell Surface Biomarker nfP2X7

“…Besides the up-regulation of P2X 7 in prostate cancer observed by other groups [39], the receptor is expressed at high level in its nonfunctional form [15,40], an example of which involved the E496A mutant [41], a mutation found to produce a loss of pore functionality [42]. Additional confirmations, many very recently, of the up-regulation of the receptor in cancer tissue have been obtained for pancreatic [43], lung [44], skin [45][46][47], brain [48,49], renal [38], prostate [50], thyroid [51], bone [52] and both ALL and AML [53,54].…”