MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT

Shen, Tao; Wang, Wei; Zhou, Wolong; Coleman, Ilsa M.; Cai, Qinbo; Dong, Bingning; Ittmann, Michael; Creighton, Chad J.; Bian, Yingnan; Meng, Yanyan; Rowley, David R.; Nelson, Peter S.; Moore, David D.; Yang, Feng Chun

doi:10.1172/jci135465

Cited by 41 publications

(44 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the present study revealed that siMAPK4 can enhance the sensitivity of HCC1937 cells to a PARP1 inhibitor, olaparib, and identified the underlying mechanism in vitro , these results require further verification in animal models and human trials. Additionally, although it is known that MAPK4 can phosphorylate AKT at both T308 and S473 in bladder urothelial carcinoma, low-grade glioma, lung adenocarcinoma, cervical cancer, thyroid carcinoma and prostate cancer ( 9 , 30 , 34 ), the present study found that only T308 was phosphorylated in TNBC cells and this was not further investigated. siRNAs can have poor stability and specificity, which may limit their usage in vivo ( 35 ).…”

Section: Discussioncontrasting

confidence: 61%

MAPK4 silencing together with a PARP1 inhibitor as a combination therapy in triple‑negative breast cancer cells

et al. 2021

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) is the most common type of cancer among females worldwide and is associated with poor prognosis. Poly ADP-ribose polymerase-1 (PARP1) inhibitors are effective against TNBC with mutations in the breast cancer type 1 susceptibility protein (BRCA1) and/or BRCA2 genes; however, the development of resistance to PARP1 inhibitors limits their use. Thus, identifying strategies to overcome this resistance is urgently required. The aim of the present study was to investigate the potential function and mechanism of small interfering (si)RNA-MAPK4 (siMAPK4) in enhancing the efficacy of a PARP1 inhibitor and reducing the resistance. In the present study, data on the mRNA expression level of MAPK4 in normal breast tissues and TNBC tissues were obtained from The Cancer Genome Atlas database. The mRNA and protein expression levels of MAPK4 in normal breast cells and TNBC cells were analyzed using reverse transcription-quantitative PCR and western blotting, respectively. The phosphorylated (p) histone H2AX (γH2AX) protein expression was assessed via immunofluorescence. Cell Counting Kit-8, wound healing and TUNEL assays were used to determine the proliferative, migratory and apoptotic abilities of HCC1937 cells. MAPK4 was highly expressed in TNBC patient tissues and cell lines. Moreover, overexpression of MAPK4 could promote HCC1937 cell proliferation. Treatment of HCC1937 cells with the combination of siMAPK4 and a PARP1 inhibitor olaparib decreased their proliferation and migration and increased their apoptosis. The protein expression levels of the DNA repair-related proteins p-DNA-dependent protein kinase catalytic subunit (DNA-PK) and RAD51 recombinase (RAD51) were inhibited in the siMAPK4 and siMAPK4 + olaparib groups. However, the marker of a double-stranded break γH2AX showed increased protein expression in the siMAPK4 + olaparib group. As MAPK4 could phosphorylate AKT at threonine 308 (AKT T308 ), the current study restored p-AKT T308 using a constitutively active AKT plasmid (AKT-CA). p-DNA-PK and RAD51 showed high expression and γH2AX exhibited lower protein expression in the AKT-CA group. The present findings suggested that siMAPK4 can enhance the sensitivity of TNBC cells to PARP1 inhibitors.

show abstract

Section: Discussioncontrasting

confidence: 61%

MAPK4 silencing together with a PARP1 inhibitor as a combination therapy in triple‑negative breast cancer cells

et al. 2021

View full text Add to dashboard Cite

show abstract

“…MAPK6 is closely related to MAPK4 ( 1 ). Since MAPK4 can directly activate AKT to promote tumor growth ( 19 , 20 ), we examined whether MAPK6 also activates AKT. To directly compare MAPK4 and MAPK6 activities in regulating AKT phosphorylation, we cotransfected FLAG-tagged AKT together with increasing doses of hemagglutinin peptide (HA)–tagged MAPK6 or HA-tagged MAPK4 into the human embryonic kidney (HEK) 293T cells.…”

Section: Resultsmentioning

confidence: 99%

MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Given that PLEK2 expression is different in the four OS cell lines assessed in the present study, and 143B cells exhibited the maximum level, whereas U-2 OS exhibited the minimum level, these cell lines were selected to comprehensively investigate the effects of PLEK2 on OS proliferation, based on previous studies ( 18 – 22 ). U-2 OS and 143B cells were transfected with a PLEK2-coding sequence and shRNA targeting PLEK2, respectively, and the mRNA and protein levels of PLEK2 following transfection were detected via RT-qPCR for knockdown (P=0.0002) and overexpression (P=0.0046; Fig.…”

Section: Resultsmentioning

confidence: 99%

PLEK2 promotes osteosarcoma tumorigenesis and metastasis by activating the PI3K/AKT signaling pathway

et al. 2021

View full text Add to dashboard Cite

Increasing evidence suggest that pleckstrin-2 (PLEK2) acts as an oncogene in several malignancies. The present study aimed to investigate the effects of PLEK2 on osteosarcoma (OS) tumorigenesis and metastasis. PLEK2 expression in OS was analyzed via bioinformatics, reverse transcription-quantitative PCR, western blot and immunohistochemistry analyses. The Cell Counting Kit-8 (CCK-8), colony formation and EdU assays were performed to assess the role of PLEK2 in OS cell proliferation. The pro-metastatic effects of PLEK2 were assessed via the Transwell and wound healing assays. In addition, the PLEK2 downstream pathway was analyzed via bioinformatics analysis and verified via western blot analysis. The results demonstrated that PLEK2 expression was upregulated in both OS cell lines and specimens. The results of the CCK-8, colony formation and EdU assays demonstrated that PLEK2 promoted OS cell proliferation in vitro. The in vivo experiments further demonstrated that PLEK2 knockdown significantly suppressed OS growth. In addition, the Transwell and wound healing assays indicated that PLEK2 promoted OS invasiveness in vitro, which was induced by the activation of the epithelial-to-mesenchymal transition process. Bioinformatics analysis revealed that PLEK2 can activate the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, which was verified via western blot analysis. Taken together, the results of the present study suggest that PLEK2 may play a tumor-promoting role in OS via the PI3K/AKT signaling pathway.

show abstract

MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT

Cited by 41 publications

References 57 publications

MAPK4 silencing together with a PARP1 inhibitor as a combination therapy in triple‑negative breast cancer cells

MAPK4 silencing together with a PARP1 inhibitor as a combination therapy in triple‑negative breast cancer cells

MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade

PLEK2 promotes osteosarcoma tumorigenesis and metastasis by activating the PI3K/AKT signaling pathway

Contact Info

Product

Resources

About