Phosphoprotein enriched in astrocytes (PEA)-15: A potential therapeutic target in multiple disease states

Greig, Fiona H.; Nixon, Graeme F.

doi:10.1016/j.pharmthera.2014.03.006

Cited by 39 publications

(37 citation statements)

References 122 publications

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“…It is a ubiquitous cytoplasmic protein involved in multiple cellular processes through its role in intracellular signaling. [44] The interactomes have common associations with several proteins in RCC and rectal cancer: CAV1, CCNB1, CDH2, COL6A1, ERCC1, FN1, KAT2A, KDR, MAP2K1, MAP2K9, RPS6 and TAZ. Unique to RCC, the PEA15 interactome proteins include: ARID1A, BCL2, BID, CD26, HSP70, JAK2, KIT, MYH11, NF2 and SQSTM1, while rectal cancer PEA15 interactome proteins include: ANXA1, BAK1, CASP3, CDK1, CDKN1A, ERCC5, ESR1, FASN, FOXM1, G6PD, LCK, MAP2K1, MSH2, RB1, STK11 and YWHAZ.…”

Section: Resultsmentioning

confidence: 99%

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Imperial

Ahmed

Toor

et al. 2018

Preprint

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To understand the molecular differences between right-sided colon cancer (RCC), left-sided colon cancer (LCC) and rectal cancer, we analyzed colorectal tumors at the DNA, RNA, miRNA and protein levels using previously sequenced data from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center. Clonal evolution analysis identified the same tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor dynamics and selection of downstream mutations were distinct in all three anatomical locations, with some similarities noted between LCC and rectal cancer. We found a potentially targetable alteration APC R1450* specific to RCC that has not been previously described. Differential gene expression analysis revealed multiple genes within the homeobox, G-protein coupled receptor binding and transcription regulation families were dysregulated in RCC, LCC, and rectal cancers and may have a pathological role in these cancers. Further, using a novel in silico proteomic analytic tool developed by our research group, we found distinct central or hub proteins with unique interactomes in each location. Protein expression signatures were not necessarily concordant with the tumor profiles obtained at the DNA and RNA levels, underscoring the relevance of post-transcriptional events in defining the biology of these cancers beyond molecular changes at the DNA and/or RNA level. Ultimately, not only tumor location and the respective genomic profile but also protein-protein interactions will need to be taken into account to improve treatment outcomes of colorectal cancers. Further studies that take into account the alterations found in this study may help in developing more tailored, and perhaps more effective, treatment strategies.Author summaryPatients with right-sided colon cancer (RCC) has a worse prognosis compared to left-sided colon cancer (LCC). Recent data has also shown that wild-type RAS metastatic RCC’s have poor outcomes when treated with the combination of chemotherapy and anti-EGFR therapy compared to LCC and rectal cancers. Therefore, There is an urgent unmet need to understand the molecular differences between RCC, LCC, and rectal cancers. In this study, we demonstrate clonal evolutionary trajectory and the order of mutations in RCC, LCC, and rectal cancers are distinct with some similarities between LCC and rectal cancers. The order of the mutations that lead to the acquisition of crucial driver alterations may have prognostic and therapeutic implications. We also discovered a novel targetable alteration, APC R1450* to be significantly enriched in early, late and metastatic RCC but not in LCC and rectal cancers. Amazingly, proteomic signatures were discordant with DNA and RNA levels. These distinct differences in DNA, RNA and post-transcriptional events may contribute to their unique clinicopathological features.Conflict of Interest StatementAshiq Masood Advisory board and speaker Bureau Bristol-Myers Squibb and Boehringer IngelheimJanakiraman Subramanian Advisory board - Astra Zeneca, Pfizer, Boehringer Ingelheim, Alexion, Paradigm, Bristol-Myers Squibb Speakers Bureau - Astra Zeneca, Boehringer Ingelheim, Lilly Research Support - Biocept and ParadigmArif Hussain Advisory board – Novartis, Bayer, Astra Zeneca Consultant – Bristol-Myers-Squibb All other authors have no conflict of interest.

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Section: Resultsmentioning

confidence: 99%

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Imperial

Ahmed

Toor

et al. 2018

Preprint

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“…As a multifunctional phosphoprotein, PEA-15 has displayed an important role in several cancer entities (6)(7)(8)(9), but its expression and function have not yet been investigated in gastric cancer. The present study demonstrated that PEA-15 was overexpressed in gastric cancer tissues and cells.…”

Section: Discussionmentioning

confidence: 99%

“…For example, PEA-15 was revealed to regulate autophagy by activating the c-Jun N-terminal kinase (JNK) pathway in glioma cells and autophagy has been revealed to be involved in drug resistance in many types of cancer (19). It is well known that PEA-15 activates ERK1/2, which participates in many biological behaviors and drug resistance of cancer cells (6,10). The initial function of PEA-15 is to mediate energy metabolism (5), which is critical for the therapy resistance of cancer cells (37).…”

Section: Discussionmentioning

confidence: 99%

“…Phosphoprotein enriched in astrocytes 15 (PEA-15), also known as phosphoprotein enriched in diabetes (PED), is ubiquitously expressed in mammals and was originally identified in primary cultured astrocytes (4). PEA-15 was initially found to play a prominent role in controlling cell survival and glucose metabolism (5), and later it was demonstrated to participate in regulating multiple biological behaviors of cells from several types of malignancies including breast and colorectal cancer, and hepatocellular carcinoma (HCC) (6)(7)(8)(9). The well-known mechanism accounting for its function is the regulation of the activation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), which mediate cell proliferation, migration and apoptosis (6,10).…”

Section: Introductionmentioning

confidence: 99%

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PEA‑15 contributes to the clinicopathology and AKT‑regulated cisplatin resistance in gastric cancer

Jiang

Zhang

et al. 2018

Oncol Rep

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Phosphoprotein enriched in astrocytes 15 (PEA-15) plays an important role in controlling biological behaviors of cancer cells. In the present study, we demonstrated that PEA-15 was overexpressed in gastric cancer tissues and associated with tumor staging, differentiation, pathological types and the prognosis of patients. Gastric cancer cells expressed variable levels of PEA-15 and its bi-phosphorylation forms, p-PEA-15 (Ser104) and p-PEA-15 (Ser116). To gain insight into the functional role of PEA-15, we generated cells stably depleted of PEA-15 and resistant to cisplatin (CDDP) from human gastric cancer cells. PEA-15 depletion inhibited cell proliferation by reducing cyclin D1 expression through the extracellular signal-regulated kinase (ERK) pathway, resulting in cell cycle arrest at the G1 phase, and induced apoptosis by activating caspase-8. PEA-15 depletion also enhanced the inhibitory effect of CDDP that caused cell cycle arrest at the S phase and also enhanced the pro-apoptotic activity of CDDP in vitro and in animal models of tumorigenesis and therapeutic effects. PEA-15 and its phosphorylated forms were overexpressed in CDDP-resistant cells, which had higher levels of p-AKT. Specific inhibition of AKT by MK2206 reduced the expression of p-PEA-15 at the Ser116 residue, resulting in sequential downregulation of p-ERK1/2, cyclin D1 and caspase-8 activation. However, depletion of PEA-15 had little effect on AKT expression or phosphorylation, or its downstream factors including p27, glycogen synthase kinase 3β and caspase-9, indicating that the regulatory effects between PEA-15 and AKT were unidirectional. In summary, the results indicated that PEA-15 expression was associated with clinicopathology and prognosis in gastric cancer and was regulated by AKT to participate in CDDP resistance, indicating that it may be a potential target for overcoming CDDP resistance in the treatment of gastric cancer.

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“…PEA15 (Proliferation and Apoptosis Adaptor Protein 15) consists of 130 amino acid residues. It performs many functions involved in broad-spectrum resistance to apoptosis [5]. Prior research reveals that it blocks Ras-mediated inhibition of integrin activation and modulates the ERK MAP kinase cascade, it also decreases RPS6KA3 activity by retaining it in the cytoplasm and suppresses Ivyspring International Publisher TNFRSF6-and TNFRSF1A regulated CASP8 activity and apoptosis [6].…”

Section: Introductionmentioning

confidence: 99%

The microRNA212 regulated PEA15 promotes ovarian cancer progression by inhibiting of apoptosis

et al. 2020

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PEA15 (Proliferation And Apoptosis Adaptor) is a 15kDa multifunctional phosphoprotein involved in various essential biological processes such as proliferation and apoptosis of cancer cells. Previous studies have demonstrated that PEA15 can promote the progression of many malignancies. In the present study, the expression of PEA15 in ovarian cancer and normal tissues analyzed in several databases and PEA15 was found to be significantly up-regulated in OC tissues compared to normal tissues. Immunochemical assays performed using 171 OC tissue specimens proved that the expression of PEA15 was remarkably positively correlated with the FIGO stage and associated with histologic subgroups of ovarian cancer. IHC assay for the two phosphorylation sites of PEA15 S116 and S104 was also performed. PEA15 high expression predicted a poor prognosis in OC patients analysed from K-M plot dataset. In addition, we proved knockdown of PEA15 inhibits OC cell proliferation and induces cell apoptosis by Bcl2 downregulation and Bax and cleaved Caspase-3 upregulation. Overexpression of PEA15 promotes the proliferative capacity of OC cells. Moreover, this study first discovered PEA15 expression in OC can be negatively regulated by microRNA212. Overexpression of miR-212 in ovarian cancer cells could cause downregulated the expression of PEA15 expression. Overexpression of miR-212 was found to exerted similar effects on the proliferation, and apoptosis of the ovarian cancer cells as that of PEA15 suppression. Additionally, overexpression of PEA15could at least partially abolished the effects of miR-212 on the proliferation, and apoptosis of ovarian cancer cells. In conclusion, our findings revealed PEA15 appears as a novel predictive biomarker, thus providing a valuable therapeutic target in OC treatment strategy.

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Phosphoprotein enriched in astrocytes (PEA)-15: A potential therapeutic target in multiple disease states

Cited by 39 publications

References 122 publications

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

PEA‑15 contributes to the clinicopathology and AKT‑regulated cisplatin resistance in gastric cancer

The microRNA212 regulated PEA15 promotes ovarian cancer progression by inhibiting of apoptosis

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