Anti-apoptotic Effects of PCP4/PEP19 in Human Breast Cancer Cell Lines: A Novel Oncotarget

Abstract

The PCP4/PEP19 is a calmodulin-binding anti-apoptotic peptide in neural cells but its potential role in human cancer has largely been unknown. We investigated the expression of PCP4/PEP19 in human breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 cells, and found that estrogen receptor (ER)-positive MCF-7 and ER-negative SK-BR-3 cells expressed PCP4/PEP19. In the MCF-7 cells, cell proliferation was estrogen-dependent, and PCP4/PEP19 expression was induced by estrogen. In both cell lines, PCP4/PEP19 knockdown induced apoptosis and slightly decreased Akt phosphorylation. Knockdown of calcium/calmodulin-dependent protein kinase kinase 1 (CaMKK1), resulting in decreased phospho-AktThr308, enhanced apoptosis in SK-BR-3 but not in MCF-7 cells. CaMKK2 knockdown moderately decreased phospho-AktThr308 and increased apoptosis in MCF-7 cells but not in SK-BR-3 cells. These data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. PCP4/PEP19 can therefore potentially serve as independent oncotarget for therapy of PCP4/PEP19-positive breast cancers irrespective of ER expression.

PCP4/PEP19 promotes migration, invasion and adhesion in human breast cancer MCF-7 and T47D cells

“…Loss of Bmi-1 has been reported to inhibit cell proliferation and enhance apoptotic cell death, which decreases Akt phosphorylation in MCF-7 cell [31]. Taken together with our previous results demonstrating that phosphorylation of Akt is reduced by PCP4/PEP19 knockdown [16], our current findings implicate PCP4/PEP19 as a novel factor in the upregulation of EMT in human breast cancer. In addition, the expression of both PCP4/PEP19 and Snail was inhibited by Bmi-1 knockdown, suggesting that PCP4/PEP19 acts downstream of the Bmi-1 signaling pathway in MCF-7 cells but not in T47D cells.…”

“…PCP4/PEP19 has an anti-apoptotic function in human breast cancer cell lines [16]. In the present study, we demonstrated that loss of PCP4/PEP19 expression decreased cell adhesion, migration, and invasion in MCF-7 and T47D human breast cancer cells.…”

“…Adherent cell areas were measured using ImageJ software. Cell apoptosis of adherent and non-adherent cells was evaluated by flow cytometry, as previously described [16]. …”

“…Our previous study showed that PCP4/PEP19 expression was increased in the mammary gland tissue of rats in which carcinogenesis was induced by exposure to 7, 12-dimethylbenz [a] anthracene exposure [15]. We also detected PCP4/PEP19 expression in human breast cancer and found that it exerts anti-apoptotic functions in human breast cancer cell lines via CaMKK and Akt signaling pathways [16]. …”

A STAT3 of Addiction: Adipose Tissue, Adipocytokine Signalling and STAT3 as Mediators of Metabolic Remodelling in the Tumour Microenvironment

“…While, the adipocytokine signaling pathway was enriched and predicted to be linked to the expression of multiple genes associated with super-enhancers in the MCF-7 model, STAT3 was not predicted to be associated with any of the super-enhancers in MCF7 compared to the MDA-MB-468 triple negative model; STAT3 was associated with all. Among the top scoring genes associated with the network pathway analysis in MDA-MB-468, unsurprisingly, most genes were associated with promotion of invasion, survival and aggressiveness [205][206][207][208][209][210][211][212][213] relative to those associated with the entire pathway activation in MCF-7 associated with inhibition of tumour suppression and [214,215], promotion of tumourigenesis, migration and survival [216][217][218][219][220][221][222][223]. Comparative downstream pathway analysis of the effect of the adipocytokine pathway in breast cancer using the SEanalysis web tool [224,225] for super enhancer associated regulatory analysis.…”