Elevated levels of Ser/Thr protein phosphatase 5 (PP5) in human breast cancer

Abstract

Ser/Thr protein phosphatase 5 (PP5) regulates several signaling-cascades that suppress growth and/or facilitate apoptosis in response to genomic stress. The expression of PP5 is responsive to hypoxia inducible factor-1 (HIF-1) and estrogen, which have both been linked to the progression of human breast cancer. Still, it is not clear if PP5 plays a role in the development of human cancer. Here, immunostaining of breast cancer tissue-microarrays (TMAs) revealed a positive correlation between PP5 over-expression and ductal carcinoma in situ (DCIS; P value 0.0028), invasive ductal carcinoma (IDC; P value 0.012) and IDC with metastases at the time of diagnosis (P value 0.0001). In a mouse xenograft model, the constitutive over-expression of PP5 was associated with an increase in the rate of tumor growth. In a MCF-7 cell culture model over-expression correlated with both an increase in the rate of proliferation and protection from cell death induced by oxidative stress, UVC-irradiation, adriamycin, and vinblastine. PP5 over-expression had no apparent effect on the sensitivity of MCF-7 cells to taxol or rapamycin. Western analysis of extracts from cells over-expressing PP5 revealed a decrease in the phosphorylation of known substrates for PP5. Together, these studies indicate that elevated levels of PP5 protein occur in human breast cancer and suggest that PP5 over-expression may aid tumor progression.

Disruption of Serine/Threonine Protein Phosphatase 5 (PP5:PPP5c) in Mice Reveals a Novel Role for PP5 in the Regulation of Ultraviolet Light-induced Phosphorylation of Serine/Threonine Protein Kinase Chk1 (CHEK1)

“…Ϫ/Ϫ MEFs Have Increased Sensitivity to UV Irradiation, Camptothecin, and Hydroxyurea-In human cells, the overexpression of PP5 provides resistance to UV-induced apoptosis, and PP5 can affect ATR-mediated checkpoint signaling (12,14,22). Therefore, we next conducted dose-response studies to determine whether the PP5-deficient 13.5-day MEFs demonstrated altered sensitivity to UV irradiation.…”

“…PP5 is expressed ubiquitously in normal tissues, and elevated PP5 protein levels are associated with the development of breast, liver, and possibly other forms of cancer (10 -15). In mouse models of tumor progression, constitutive PP5 overexpression aids tumor growth but does not induce spontaneous tumor formation (12)(13)(14). At the molecular level, PP5 is found in multiprotein complexes.…”

Knockdown of serine/threonine protein phosphatase 5 enhances gemcitabine sensitivity by promoting apoptosis in pancreatic cancer cells in�vitro

“…It has been reported that PPP5C serves an important role in glioma metastasis, as downregulation of PPP5C mitigated cell migration in U251 and U373 cell lines (34). In human breast cancer, a strong association was observed between high levels of PPP5C expression and the occurrence of invasive ductal carcinoma in patients with metastatic disease at the time of diagnosis (45). In rats, PPP5C mRNA levels markedly increased in malignant ascites hepatomas (46).…”

“…In particular, PPP5 has been revealed to act as a suppressor of ASK (48,49), p53 and DNA-dependent protein kinase, catalytic subunit (45). PPP5C appears to interact with ASK1, which is associated with the c-JNK and p38 signaling pathways.…”

Development and Validation of a Robust and Sensitive Assay for the Discovery of Selective Inhibitors for Serine/Threonine Protein Phosphatases PP1α (PPP1C) and PP5 (PPP5C)

“…Aberrant PP1 activity has been linked to a number of human ailments, 7,11,12,[25][26][27] and many studies of PP5 function indicate pivotal roles in the regulation of cellular proliferation and stressinduced apoptosis that serve to validate it as an antitumor drug target. 7,[28][29][30][31][32][33][34][35] However, to date there are no reports of small-molecule inhibitors that can be used to distinguish the activity of PP1 versus PP5. Therefore, selective inhibitors of PP1 or PP5 are desired as probes to further characterize the biology associated with these enzymes, and specific or highly selective inhibitors may also serve as lead compounds for drug development.…”