PEA-15 Inhibits Tumorigenesis in an MDA-MB-468 Triple-Negative Breast Cancer Xenograft Model through Increased Cytoplasmic Localization of Activated Extracellular Signal-Regulated Kinase

Bartholomeusz, Chandra; González-Angulo, Ana M.; Kazansky, Anna; Krishnamurthy, Savitri; Liu, Ping; Yuan, Linda X.H.; Yamasaki, Fumiyuki; Liu, Shuying; Hayashi, Naoki; Zhang, Dongwei; Esteva, Francisco J.; Hortobágyi, Gabriel N.; Ueno, Naoto T.

doi:10.1158/1078-0432.ccr-09-1456

Cited by 38 publications

(41 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding is consistent with recent reports regarding the role of PEA-15 in activating cell death in breast cancer cells (Bartholomeusz et al, 2010). (Bartholomeusz et al, 2010). We discovered that the function of PEA-15 in mediating G129R-induced autophagy requires stabilization of the protein.…”

Section: Discussionsupporting

confidence: 94%

See 1 more Smart Citation

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

et al. 2014

Self Cite

View full text Add to dashboard Cite

Summary Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism for cell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets because of their roles as growth factors in tumor growth and progression. We utilized a novel antagonist peptide of PRL, G129R, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced accumulation of redundant autolysosomes in three-dimensional cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a non-canonical beclin-1–independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR in clinical samples were associated with longer patient survival. Our findings provide a new understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications.

show abstract

Section: Discussionsupporting

confidence: 94%

“…The PEA-15 siRNA (ggaagacauccccagcgaatt) was described previously (Bartholomeusz et al, 2010). Adenoviral PEA-15 (Ad.PEA-15) was constructed by inserting PEA-15 cDNA into the adenoviral vector pAdTrack-CMV (He et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, whereas we were evaluating the effect of PEA15 on RAS-mediated transformation, the previous study was assessing the effect of PEA15 on RAS-transformed cells. Consistent with our results, several previous studies have shown that expression of PEA15 blocks tumor cell growth (46)(47)(48).…”

Section: Discussionsupporting

confidence: 93%

PEA15 Regulates the DNA Damage-Induced Cell Cycle Checkpoint and Oncogene-Directed Transformation

Nagarajan

Dogra

Liu

et al. 2014

Molecular and Cellular Biology

View full text Add to dashboard Cite

cRegulation of the DNA damage response and cell cycle progression is critical for maintaining genome integrity. Here, we report that in response to DNA damage, COPS5 deubiquitinates and stabilizes PEA15 in an ATM kinase-dependent manner. PEA15 expression oscillates throughout the cell cycle, and the loss of PEA15 accelerates cell cycle progression by activating CDK6 expression via the c-JUN transcription factor. Cells lacking PEA15 exhibit a DNA damage-induced G 2 /M checkpoint defect due to increased CDC25C activity and, consequentially, higher cyclin-dependent kinase 1 (CDK1)/cyclin B activity, and accordingly they have an increased rate of spontaneous mutagenesis. We find that oncogenic RAS inhibits PEA15 expression and that ectopic PEA15 expression blocks RAS-mediated transformation, which can be partially rescued by ectopic expression of CDK6. Finally, we show that PEA15 expression is downregulated in colon, breast, and lung cancer samples. Collectively, our results demonstrate that tumor suppressor PEA15 is a regulator of genome integrity and is an integral component of the DNA damage response pathway that regulates cell cycle progression, the DNA-damage-induced G 2 /M checkpoint, and cellular transformation.T he conversion of a normal cell to a cancer cell requires multiple genetic and epigenetic alterations. These changes include the activation of oncogenes and inactivation of tumor suppressor genes. Although oncogenes are expected to exert proliferative effects, paradoxically, introduction of an oncogene in primary mouse or human cells can induce a state similar to replicative senescence, which is referred to as oncogene-induced senescence.Oncogene-induced senescence is a mechanism that is believed to prevent neoplastic transformation (1, 2). Cells undergoing oncogene-induced senescence display characteristic hallmarks of replicative senescence (3) but with a much more rapid onset. Several mechanisms of oncogene-induced senescence have been proposed (3). One of the proposed mechanisms is that oncogenes can cause DNA replication stress, which activates the DNA damage response (DDR) pathway, leading to oncogene-induced senescence (4, 5). These studies suggest that proteins that mediate oncogene-induced senescence might also regulate the DNA damage response pathway and thereby function as tumor suppressors. In good agreement with this view, tumor suppressor proteins, such as p53, that play an important role in oncogene-induced senescence have been shown to regulate DNA damage checkpoints and DNA repair to maintain genome integrity, a function that is necessary for p53 to prevent neoplastic transformation (6-8).We previously performed a genome-wide RNA interference (RNAi) screen for mediators of oncogenic BRAF-induced cellular senescence (9) and identified 17 genes. One of the genes identified from our RNAi screen was the protein enriched in astrocytes 15 (PEA15). PEA15 is a multifunctional protein that has been implicated in diverse biological processes and regulates several signaling pathways (10). Notabl...

show abstract

“…The PEA-15 siRNA (ggaagacauccccagcgaatt) was described previously (15). The EGFP-LC3 plasmid was derived from Addgene 11546(16).…”

Section: Methodsmentioning

confidence: 99%

Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer

Wen

Graybill

Previs

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized monoclonal antibody against FRα, in ovarian cancer models. Experimental Design We first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003–induced cell death. Results MORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In add, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cystadenocarcinoma. Conclusions MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation.

show abstract

PEA-15 Inhibits Tumorigenesis in an MDA-MB-468 Triple-Negative Breast Cancer Xenograft Model through Increased Cytoplasmic Localization of Activated Extracellular Signal-Regulated Kinase

Cited by 38 publications

References 23 publications

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

PEA15 Regulates the DNA Damage-Induced Cell Cycle Checkpoint and Oncogene-Directed Transformation

Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer

Contact Info

Product

Resources

About