MAPK4 deletion enhances radiation effects and triggers synergistic lethality with simultaneous PARP1 inhibition in cervical cancer

Tian, Shuzhen; Lou, Li‐Li; Tian, Mengyuan; Lu, Guangping; Tian, Jianghua; Chen, Xi

doi:10.1186/s13046-020-01644-5

Cited by 23 publications

(16 citation statements)

References 38 publications

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“…MAPK4 is an oncogene that is upregulated in numerous types of cancer and contributes to poor prognosis. For instance, in cervical cancer, high MAPK4 mRNA expression is associated with a lower survival rate ( 31 ). The present data indicated that MAPK4 was highly expressed in patients with TNBC, suggesting that downregulating MAPK4 expression may enhance the effect of PARP1 inhibitors on TNBC.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, the present study investigated the mechanism underlying how siMAPK4 enhances the sensitivity of TNBC cells to olaparib. Previous studies have reported that MAPK4 can phosphorylate AKT at T308 and S473 without influencing total AKT levels, thereby enhancing the efficacy of PARP1 inhibitors by suppressing the repair of radiation-induced DNA damage in cervical cancer cell lines ( 9 , 31 ). Nevertheless, the current data indicated that MAPK4 could only activate AKT T308 in HCC1937 cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Combined treatment including MAPK4 silencing and the PARP1 inhibitor olaparib inhibited cell proliferation and promoted apoptosis in these cells [29]. Also, in cervical cancer cells, MAPK4 knockdown and PARP1 inhibition exerted synergistic effects by activating AKT phosphorylation [32]. This suggests that the observed synergy between niraparib and the phytocannabinoids occurs because suppression of MAPK4 expression that enhances the PARP inhibitor cytotoxic activity on OC cells.…”

Section: Discussionmentioning

confidence: 99%

Δ9–Tetrahydrocannabinol (THC)-Rich Compositions from Cannabis Have Cytotoxic Activity Against Ovarian Cancer Cells and Act Synergistically With Niraparib in vitro

Shalev¹,

Kendall²,

Anil³

et al. 2021

Preprint

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Ovarian cancer (OC) is the most lethal gynecologic malignancy. Cannabis sativa is being used to treat different medical conditions. We sought to examine the effectiveness of combinations of cannabis compounds against OC. Cytotoxic activity was determined by XTT assay on HTB75 and HTB161 cell lines. Apoptosis and cell cycle were determined by fluorescence-activated cell sorting (FACS). Gene expression was determined by quantitative PCR. The two most active fractions, F5 and F7, from a high Δ9–tetrahydrocannabinol (THC) cannabis strain extract and their standard mix (SM) showed cytotoxic activity against OC cells. The most effective phytocannabinoid combination was THC+cannabichromene (CBC)+cannabigerol (CBG). F5, F7 and SM affected cell cycle, led to cell apoptosis and to a marked reduction in cell migration. Moreover, these fractions act in synergy with niraparib, and were ~50 fold more cytotoxic to OC cells than to normal keratenocytes. Niraparib+F7 treatment was effective on OC patient's cells. F7 and the niraparin+fraction (F5 and F7) treatments reduced Mitogen-Activated Protein Kinase 4 (MAPK4) gene expression; this reduction may act in synergy with the niraparib inhibition of Poly (ADP-ribose) polymerase 1 (PARP1) activity. Combinations of cannabis compounds and niraparib should be examined for efficacy in pre-clinical studies and clinical trials.

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“…The 8505C cells were incubated with 0, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 μM doxorubicin; CAL-62 cells were incubated with 0, 0.02, 0.04, 0.08, 0.16, 0.32, and 0.64 μM doxorubicin; and 8505C/Dox cells were incubated with 0, 2, 4, 8, 16, 32, and 64 μM doxorubicin ( 15 , 16 ). After 48 h of treatment, CCK-8 assay was performed by the methods mentioned in the Cell Viability Assay subsection and half maximal inhibitory concentration (IC 50 ) was calculated using the sigmoidal dose–response function of the GraphPad Prism software (Version 7.0) ( 17 ).…”

Section: Methodsmentioning

confidence: 99%

A-Kinase Interacting Protein 1 Knockdown Restores Chemosensitivity via Inactivating PI3K/AKT and β-Catenin Pathways in Anaplastic Thyroid Carcinoma

2022

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BackgroundA-kinase interacting protein 1 (AKIP1) promotes tumor progression and chemoresistance in several malignancies; meanwhile, it is related to higher tumor size and recurrence risk of papillary thyroid carcinoma, while the role of AKIP1 in anaplastic thyroid carcinoma (ATC) is unclear. The aim of this study is to explore the effect of AKIP1 knockdown on cell malignant behaviors and doxorubicin resistance in ATC.MethodsAKIP1 knockdown was conducted in ATC cell lines (8505C and CAL-62 cells) by siRNA; then, cell viability, apoptosis, invasion, PI3K/AKT and β-catenin pathways, and doxorubicin sensitivity were detected. Subsequently, doxorubicin-resistant 8505C cells (8505C/Dox) were established. Additionally, AKIP1 was modified in 8505C and 8505C/Dox cells that underwent doxorubicin treatment by siRNA or overexpression plasmid, followed by cellular function and pathway detection.ResultsAKIP1 was elevated in FRO, 8505C, CAL-62, and KHM-5M cells compared to control cells (all p < 0.05). Subsequently, AKIP1 knockdown elevated apoptosis, inhibited viability and invasion, and inactivated PI3K/AKT and β-catenin pathways in 8505C and CAL-62 cells (all p < 0.05). AKIP1 knockdown decreased relative cell viability in doxorubicin-treated 8505C and CAL-62 cells; then, AKIP1 was elevated in 8505C/Dox cells compared to 8505C cells (all p < 0.05). Furthermore, AKIP1 knockdown restored doxorubicin sensitivity (reflected by decreased cell viability and invasion, and increased apoptosis), but inactivated PI3K/AKT and β-catenin pathways in doxorubicin-treated 8505C/Dox cells. However, AKIP1 overexpression presented an opposite effect on these functions and pathways in doxorubicin-treated 8505C cells.ConclusionAKIP1 knockdown decreases cell survival and invasion while promoting sensitivity to doxorubicin via inactivating PI3K/AKT and β-catenin pathways in ATC.

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MAPK4 deletion enhances radiation effects and triggers synergistic lethality with simultaneous PARP1 inhibition in cervical cancer

Cited by 23 publications

References 38 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

Δ9–Tetrahydrocannabinol (THC)-Rich Compositions from Cannabis Have Cytotoxic Activity Against Ovarian Cancer Cells and Act Synergistically With Niraparib in vitro

A-Kinase Interacting Protein 1 Knockdown Restores Chemosensitivity via Inactivating PI3K/AKT and β-Catenin Pathways in Anaplastic Thyroid Carcinoma

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