hPEBP4 Resists TRAIL-induced Apoptosis of Human Prostate Cancer Cells by Activating Akt and Deactivating ERK1/2 Pathways

Abstract

The treatment options available for prostate cancer are limited because of its resistance to therapeutic agents. Thus, a better understanding of the underlying mechanisms of the resistance of prostate cancer will facilitate the discovery of more efficient treatment protocols. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is recently identified by us as an anti-apoptotic molecule and a potential candidate target for breast cancer treatment. Here we found the expression levels of hPEBP4 were positively correlated with the severity of clinical prostate cancer. Furthermore, hPEBP4 was not expressed in TRAIL-sensitive DU145 prostate cancer cells, but was highly expressed in TRAIL-resistant LNCaP cells, which show highly activated Akt. Interestingly, hPEBP4 overexpression in TRAILsensitive DU145 cells promoted Akt activation but inhibited ERK1/2 activation. The hPEBP4-overexpressing DU145 cells became resistant to TRAIL-induced apoptosis consequently, which could be reversed by PI3K inhibitors. In contrast, silencing of hPEBP4 in TRAIL-resistant LNCaP cells inhibited Akt activation but increased ERK1/2 activation, resulting in their sensitivity to TRAIL-induced apoptosis that was restored by the MEK1 inhibitor. Therefore, hPEBP4 expression in prostate cancer can activate Akt and deactivate ERK1/2 signaling, leading to TRAIL resistance. We also demonstrated that hPEBP4-mediated resistance to TRAIL-induced apoptosis occurred downstream of caspase-8 and at the level of BID cleavage via the regulation of Akt and ERK pathways, and that hPEBP4-regulated ERK deactivation was upstream of Akt activation in prostate cancer cells. Considering that hPEBP4 confers cellular resistance to TRAIL-induced apoptosis and is abundantly expressed in poorly differentiated prostate cancer, silencing of hPEBP4 suggests a promising approach for prostate cancer treatment.Prostate cancer is the most common malignancy and one of the leading causes of cancer mortality in men. The development of human prostate cancer has been viewed as a multistage process, involving the onset as small latent carcinoma of low histological grade to large metastatic lesion of higher grade. Unfortunately, chemotherapy and radiation therapy are not effective for prostate cancer patients. Therefore, a better understanding of molecular mechanisms for the resistance of prostate cancer cells to therapeutic agents will be useful to explore more efficient treatment protocols. Multiple signaling pathways govern the progression of prostate cancer, and the two most significant and well investigated pathways are the phosphatidylinositol 3-kinase (PI3K) 3 /Akt and MAPK pathways (1, 2).ThePI3K/Aktpathwaymediatessurvivalsignalsinandrogendependent and -independent prostate tumor cell lines, and controls the progression of prostate cancer to an androgenindependent state (1). The activation of ERK1/2 is detectable in premalignant lesions and/or early stage cancers; hence, it may play a role in the pathogenesis or early progression of prostate cancer (3, 4). It has been sho...

Human Phosphatidylethanolamine-binding Protein 4 Promotes Transactivation of Estrogen Receptor α (ERα) in Human Cancer Cells by Inhibiting Proteasome-dependent ERα Degradation via Association with Src

“…Normally colocalizing with lysosome, hPEBP4 translocates to the cell membrane upon TNF-␣ stimulation, where it binds to Raf-1 and MEK1 (10). hPEBP4 appears to promote cellular resistance to TNF-␣/tumor necrosis factorrelated apoptosis-inducing ligand-induced apoptosis by inhibiting activation of JNK (c-Jun N-terminal kinase) and the Raf-1/MEK/ERK pathway (11)(12)(13). However, it is almost impossible to imagine that TNF-␣ or tumor necrosis factor-related apoptosis-inducing ligand can accumulate to a concentration high enough to kill tumor cells in vivo, let alone the determined association of TNF-␣ for patients with a poor prognosis of tumors.…”

Raf kinase inhibitory protein: a signal transduction modulator and metastasis suppressor

“…Surprisingly, RKIP regulation of NFκB and sensitivity to death ligands was not observed in nontumor cells, raising questions regarding the generality of this effect and whether the potentiation of death results indirectly from RKIP overexpression. To confuse matters more, hPEBP4, a related family member, was reported to block TRAIL and TNFα-induced apoptosis even though it also inhibits Raf/MAPK signaling [46]. Therefore the normal physiological role of the PEBP family in regulating immune surveillance by the TNFα family is presently unclear.…”

Potentiation of Tumor Necrosis Factor-α-induced Tumor Cell Apoptosis by a Small Molecule Inhibitor for Anti-apoptotic Protein hPEBP4

“…Apoptosis by IOI-42-hPEBP4 is regarded as an anti-apoptotic protein for its role in apoptosis resistance of tumor cells to TNF-␣ and TRAIL (10,16,17). Thus, we wondered whether IOI-42 could potentiate TNF-␣-induced tumor cell apoptosis.…”

“…Because hPEBP4 has been proved to play a role in the resistance of tumor cells to the apoptosis induction by TRAIL as well (17,18), we then tested whether IOI-42 could sensitize LNCaP cells to TRAIL-induced apoptosis. LNCaP is a human prostate cancer cell line with high expression of hPEBP4 and resistance to TRAIL-induced apoptosis, while IOI-42 pretreatment significantly potentiated TRAIL-induced apoptosis of LNCaP cells than when TRAIL used alone (Fig.…”

“…Considering that hPEBP4 is particularly abundant in tumor tissues (16,17) and potentiates resistance to TNF-␣-and TRAIL-induced apoptosis in certain kinds of cancer cells. In this study, we aimed to find a lead compound that specifically targets hPEBP4 to inhibit its anti-apoptotic function and subsequently increase the sensitivity of cancer cells to the killing of chemical drugs.…”