Liprin-α4 as a Possible New Therapeutic Target for Pancreatic Cancer

Yamasaki, Akio; Nakayama, Kouji; Imaizumi, Akira; Kawamoto, Makoto; Fujimura, Akiko; Oyama, Yoshie; Nagai, Sonoko; Yanai, Kosuke; Onishi, Hideya

doi:10.21873/anticanres.12122

Cited by 8 publications

(8 citation statements)

References 13 publications

(22 reference statements)

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“…MiR-34a, a tumor suppressor miRNA, inhibited the progressive phenotypes of PCa cells via directly regulating STMN1 (45). PPFIA4 belongs to the liprin-alpha gene family and inhibition of PPFIA4 reduced pancreatic cancer cell proliferation and invasion (46). Moreover, suppression of PPFIA4 promoted chemosensitivity of small lung cancer (SCL) cells under hypoxia (47).…”

Section: Discussionmentioning

confidence: 99%

A Glycolysis-Related Five-Gene Signature Predicts Biochemical Recurrence-Free Survival in Patients With Prostate Adenocarcinoma

Liu

et al. 2021

Front. Oncol.

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Prostate cancer (PCa) is one of the most frequently diagnosed cancers in males worldwide. Approximately 25% of all patients experience biochemical recurrence (BCR) after radical prostatectomy (RP) and BCR indicates increased risk for metastasis and castration resistance. PCa patients with highly glycolytic tumors have a worse prognosis. Thus, this study aimed to explore glycolysis-based predictive biomarkers for BCR. Expression data and clinical information of PCa samples were retrieved from three publicly available datasets. One from The Cancer Genome Atlas (TCGA) dataset was used as the training cohort, and two from the Gene Expression Omnibus (GEO) dataset (GSE54460 and GSE70769) were used as validation cohorts. Using the training cohort, univariate Cox regression survival analysis, robust likelihood-based survival model, and stepwise multiply Cox analysis were sequentially applied to explore predictive glycolysis-related candidates. A five-gene risk score was then constructed based on the Cox coefficient as the following: (−0.8367*GYS2) + (0.3448*STMN1) + (0.3595*PPFIA4) + (−0.1940*KDELR3) + (0.4779*ABCB6). Receiver operating characteristic curve (ROC) analysis was used to identify the optimal cut-off point, and patients were divided into low risk and high risk groups. Kaplan–Meier analysis revealed that high risk group had significantly shorter BCR free survival time as compared with that in low risk group in training and validation cohorts. In conclusion, our data support the glycolysis-based five-gene signature as a novel and robust signature for predicting BCR of PCa patients.

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Section: Discussionmentioning

confidence: 99%

A Glycolysis-Related Five-Gene Signature Predicts Biochemical Recurrence-Free Survival in Patients With Prostate Adenocarcinoma

Liu

et al. 2021

Front. Oncol.

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“…Within those DEGs unique to control-iPSC, we found PPFIA4 (also known as Liprin-α4), ceruloplasmin (CP), and stanniocalcin-1 (STC1), which were increased 13.6-fold, 77-fold, and fivefold, respectively, under 2% oxygen, only in control iPSC-derived trophoblast ( Supplementary Figure 4). Both liprin-α4 and STC1 have been shown to promote invasion of cancer cells [51][52][53] , while secretion of ceruloplasmin in the placenta is known to be induced by hypoxia 54 . Another interesting gene in this group was ARNT (aryl hydrocarbon receptor nuclear translocator; also called "HIF1β"), which showed a statistically-significant (adjusted p value < 0.05), albeit modest (1.3-fold), increase only in control-iPSC ( Supplementary Figure 4).…”

Section: Global Gene Expression In Pe and Control Ipsc-derived Trophomentioning

confidence: 99%

Modeling preeclampsia using human induced pluripotent stem cells

Horii

Morey

Bui

et al. 2021

Sci Rep

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Preeclampsia (PE) is a pregnancy-specific hypertensive disorder, affecting up to 10% of pregnancies worldwide. The primary etiology is considered to be abnormal development and function of placental cells called trophoblasts. We previously developed a two-step protocol for differentiation of human pluripotent stem cells, first into cytotrophoblast (CTB) progenitor-like cells, and then into both syncytiotrophoblast (STB)- and extravillous trophoblast (EVT)-like cells, and showed that it can model both normal and abnormal trophoblast differentiation. We have now applied this protocol to induced pluripotent stem cells (iPSC) derived from placentas of pregnancies with or without PE. While there were no differences in CTB induction or EVT formation, PE-iPSC-derived trophoblast showed a defect in syncytialization, as well as a blunted response to hypoxia. RNAseq analysis showed defects in STB formation and response to hypoxia; however, DNA methylation changes were minimal, corresponding only to changes in response to hypoxia. Overall, PE-iPSC recapitulated multiple defects associated with placental dysfunction, including a lack of response to decreased oxygen tension. This emphasizes the importance of the maternal microenvironment in normal placentation, and highlights potential pathways that can be targeted for diagnosis or therapy, while absence of marked DNA methylation changes suggests that other regulatory mechanisms mediate these alterations.

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“…Moreover, As the intracellular effectors of receptor protein tyrosine phosphatase-leukocyte antigen related receptor F (LAR-RPTP), PPFIA4 interacts with the catalytically inactive D2 domain of LAR-RPTP via their highly conserved C-terminal three sterile alpha motif domains and promotes its phosphatase activity [ 49 ]. There is emerging evidence indicating that PPFIA4 plays an important role in several malignancies including refractory pancreatic cancer [ 20 ], small cell lung cancer [ 21 ], and clear cell renal cell cancer [ 18 ]. In this study, we clearly demonstrated that PPFIA4 could promote CRPC progression by enhancing the mitochondrial function of PCa cells and served as a novel regulator for mitochondrial function in CRPC progression.…”

Section: Discussionmentioning

confidence: 99%

“…Liprin-α4 (encoded by PPFIA4), a member of liprin-α family, has been found in various multiprotein complexes [ 18 , 19 ]. It has been reported as a new potential therapeutic target for refractory pancreatic cancer [ 20 ], small cell lung cancer [ 21 ], and clear cell renal cell cancer [ 18 ]. Additionally, PPFIA4 has been reported in several studies to be potentially associated with aberrant metabolic processes [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

PPFIA4 promotes castration-resistant prostate cancer by enhancing mitochondrial metabolism through MTHFD2

Zhao

Feng

Gao

et al. 2022

J Exp Clin Cancer Res

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Background The development of castration-resistant prostate cancer (CRPC) remains a major obstacle in the treatment of prostate cancer (PCa). Dysregulated mitochondrial function has been linked to the initiation and progression of diverse human cancers. Deciphering the novel molecular mechanisms underlying mitochondrial function may provide important insights for developing novel therapeutics for CRPC. Methods We investigate the expression of the protein tyrosine phosphatase receptor type F polypeptide interacting protein alpha 4 (PPFIA4) using public datasets and tumor specimens from PCa cases by immunohistochemistry. Gain- and loss-of-function studies are performed in PCa cell lines and mouse models of subcutaneous xenograft to characterize the role of PPFIA4 in CRPC. Gene expression regulation is evaluated by a series of molecular and biochemical experiments in PCa cell lines. The therapeutic effects of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) inhibitor combined enzalutamide are assessed using in vitro functional assays and in vivo mouse models. Results We show that the increase of PPFIA4 exacerbates aggressive phenotype resembling CRPC. A fraction of PPFIA4 localizes to mitochondria and interacts with MTHFD2, a key enzyme for one-carbon metabolism. Androgen deprivation increases the translocation of PPFIA4 into mitochondria and increases the interaction between PPFIA4 and MTHFD2, which result in the elevation of tyrosine phosphorylated MTHFD2. Consequently, the levels of NADPH synthesis increase, resulting in protection against androgen deprivation-induced mitochondrial dysfunction, as well as promotion of tumor growth. Clinically, PPFIA4 expression is significantly increased in CRPC tissues compared with localized PCa ones. Importantly, an MTHFD2 inhibitor, DS18561882, combined with enzalutamide can significantly inhibit CRPC cell proliferation in vitro and tumor growth in vivo. Conclusion Overall, our findings reveal a PPFIA4-MTHFD2 complex in mitochondria that links androgen deprivation to mitochondrial metabolism and mitochondrial dysfunction, which suggest a potential strategy to inhibit CRPC progression.

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Liprin-α4 as a Possible New Therapeutic Target for Pancreatic Cancer

Abstract: Liprin-α4 plays a pivotal role in inducing malignant phenotypes such as increased proliferation and invasion in pancreatic cancer, and that liprin-α4 could be a new effective therapeutic target for pancreatic cancer.

Cited by 8 publications

References 13 publications

A Glycolysis-Related Five-Gene Signature Predicts Biochemical Recurrence-Free Survival in Patients With Prostate Adenocarcinoma

A Glycolysis-Related Five-Gene Signature Predicts Biochemical Recurrence-Free Survival in Patients With Prostate Adenocarcinoma

Modeling preeclampsia using human induced pluripotent stem cells

PPFIA4 promotes castration-resistant prostate cancer by enhancing mitochondrial metabolism through MTHFD2

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