TGM2 knockdown reverses cisplatin chemoresistance in osteosarcoma

Li, Cuiyun; Cai, Jing; Fu-gui, GE; Wang, Guilong

doi:10.3892/ijmm.2018.3753

Cited by 23 publications

(24 citation statements)

References 34 publications

(38 reference statements)

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“…Regarding the multifactorial resistance profile, the present study aimed to investigate other potential signaling pathways involved in cisplatin sensitivity induced by MET in addition to mTOR signaling. In both sensitive and resistant cells, MET altered transcriptional processes, regulated apoptosis, oxidation-reduction processes and proteins associated with leukocyte degranulation, with 99 common significantly altered targets, of which some have been previously described: AK3 ( 68 ), ALDH1A1 ( 69 ), ANXA2 and 4 ( 70 , 71 ), CFL1 ( 72 ), CRYAB ( 73 ), filamin A (FLNA) ( 74 ), GSTP1 ( 75 ), HMGA1 and G6PD ( 76 ), hnRNPA2B1 ( 77 ), HSP90 ( 78 ), IGF2BP1 ( 79 ), integrin b1 (ITGB1) ( 80 ), MYH9 ( 81 ), PKM2 ( 82 - 84 ), STIP1 ( 85 ), TGM2 ( 86 ), TKT ( 87 ) and TRAP1 ( 88 ).…”

Section: Discussionmentioning

confidence: 99%

Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways

et al. 2021

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Lung cancer is the leading cause of cancer-associated death worldwide and exhibits intrinsic and acquired therapeutic resistance to cisplatin (CIS). The present study investigated the role of mTOR signaling and other signaling pathways after metformin (MET) treatment in control and cisplatin-resistant A549 cells, mapping pathways and possible targets involved in CIS sensitivity. MTT, flow cytometry, clonogenic assay, western blotting, proteomic analysis using the Stable Isotope Labeling by Amino acids in Cell culture (SILAC) approach and reverse transcription-quantitative PCR were performed. The results revealed that CIS treatment induced mTOR signaling pathway overactivation, and the mTOR status was restored by MET. MET and the mTOR inhibitor rapamycin (RAPA) decreased the viability in control and resistant cells, and decreased the cell size increase induced by CIS. In control cells, MET and RAPA decreased colony formation after 72 h and decreased IC 50 values, potentiating the effects of CIS. Proteomics analysis revealed important pathways regulated by MET, including transcription, RNA processing and IL-12-mediated signaling. In CIS-resistant cells, MET regulated the apoptotic process, oxidative stress and G 2 /M transition. Annexin 4 (ANXA4) and superoxide dismutase 2 (SOD2), involved in apoptosis and oxidative stress, respectively, were chosen to validate the SILAC analysis and may represent potential therapeutic targets for lung cancer treatment. In conclusion, the chemosensitizing and antiproliferative effects of MET were associated with mTOR signaling and with potential novel targets, such as ANXA4 and SOD2, in human lung cancer cells.

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Section: Discussionmentioning

confidence: 99%

Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways

et al. 2021

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“…TGM2, a cross-linking enzyme, has been demonstrated to be tightly associated with chemosensitivity in diverse cancers [ 38 , 39 ]. Moreover, previous study revealed that TGM2 expression was enhanced in cisplatin-resistant OS cells and its deficiency elevated the chemosensitivity of osteosarcoma to cisplatin [ 23 ]. Therefore, we wondered whether TGM2 participated in MTX resistance of OS.…”

Section: Discussionmentioning

confidence: 99%

“…Besides, previous report revealed that TGM2 promoted the progression of osteosarcoma [ 22 ]. Moreover, TGM2 was also reported to be related to chemoresistance in multiple cancers [ 23 , 24 ]. Nevertheless, there is no evidence that TGM2 plays a role and the relationship between TGM2 and miR-494-3p in MTX sensitivity of OS.…”

Section: Introductionmentioning

confidence: 99%

Circular RNA circ_0081001 knockdown enhances methotrexate sensitivity in osteosarcoma cells by regulating miR-494-3p/TGM2 axis

Wei

Duan

et al. 2021

J Orthop Surg Res

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Background Circular RNAs (circRNAs) have been shown to participate in the chemoresistance and tumorigenesis of multiple cancers. The purpose of this research was to investigate the function of circ_0081001 in methotrexate (MTX) resistance of osteosarcoma (OS) and its potential molecular mechanism. Methods The expression of circ_0081001, cytochrome P450 family 51 subfamily A member 1 (CYP51A1), and miR-494-3p was detected by qRT-PCR. Cell viability, apoptosis, migration, and invasion were evaluated by Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and transwell assay, respectively. Western blot (WB) assay was used to measure the protein levels of cleaved-caspase3 (cleaved-casp3), E-cadherin, N-cadherin, and transglutaminase-2 (TGM2). The interaction between miR-494-3p and circ_0081001 or TGM2 was predicted by bioinformatics analysis and verified using the dual-luciferase reporter assay. The mice xenograft model was established to investigate the roles of circ_0081001 in MTX resistance of OS in vivo. Results Circ_0081001 and TGM2 were upregulated, and miR-494-3p was downregulated in MTX-resistant OS tissues and cells. Moreover, circ_0081001 interference enhanced cell sensitivity to MTX through promoting apoptosis and inhibiting cell viability and metastasis in vitro. Furthermore, circ_0081001 was identified as a molecular sponge of miR-494-3p to upregulate TGM2 level. In addition, circ_0081001 knockdown inhibited MTX resistance via upregulating miR-494-3p and downregulating TGM2. Besides, circ_0081001 downregulation improved MTX sensitivity of OS in vivo. Conclusion Knockdown of circ_0081001 enhanced MTX sensitivity of OS cells through downregulating TGM2 by sponging miR-494-3p, elucidating a novel regulatory mechanism for chemoresistance of OS and providing a potential circRNA-targeted therapy for OS.

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“…Suppressing TGM2 expression can promote meningioma cell death by reducing AKT phosphorylation and caspase-3 ( 34 ), while AKT activation may drive normal breast mammary epithelial MCF10A cells into EMT via TG2 signaling ( 35 ). Moreover, TGM2 silencing can suppress AKT activation in the Saos2-cIS-R cells ( 36 ). All these data suggest that the reduced expression of TG2(TGM2)/AKT may promote the drug sensitivity of cancer cells via EMT reversal.…”

Section: Discussionmentioning

confidence: 99%

miR‑125a‑5p reverses epithelial‑mesenchymal transition and restores drug sensitivity by negatively regulating TAFAZZIN signaling in breast cancer

Chen

Zhang

et al. 2021

Mol Med Rep

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MicroRNA (miR)-125a-5p represses tafazzin phospholipid-lysophospholipid transacylases (TAFAZZIN) expression and inhibits the epithelial-mesenchymal transition (EMT) of ovarian cancer cells. EMT was found to have a crucial role in the acquisition of chemoresistance. Thus, the present study aimed to determine whether miR-125a-5p reverses EMT and restores drug sensitivity by negatively regulating TAFAZZIN in breast cancer. The expression of miR-125a-5p/TAFAZZIN and its association with chemotherapy response were determined in tissue samples from patients with breast cancer. Furthermore, the effects of miR-125a-5p on breast cancer cells were elucidated using cell proliferation and cell apoptosis assays. Then, the regulatory mechanism of miR-125a-5p in breast cancer was investigated by reverse transcription-quantitative PCR, western blotting, dual-luciferase reporter and RNA immunoprecipitation assays. The results demonstrated that miR-125a-5p inhibited the EMT of MCF-7/adriamycin (Adr) breast cancer cells, as well as decreased the proliferation and increased the apoptosis of breast cancer cells treated with Adr/docetaxel. In addition, miR-125a-5p downregulated the expression levels of TAFAZZIN, Transglutaminase 2, phosphorylated-AKT, N-cadherin, vimentin and proliferating cell nuclear antigen, and significantly increased those of E-cadherin, cleaved caspase-3 and Bax in MCF7/Adr cells. Similar results were obtained with small interfering RNA-TAFAZZIN. Moreover, TAFAZZIN was identified as a direct target of miR-125a-5p in MCF7/Adr breast cancer cells. In addition, increased miR-125a-5p expression was observed in breast tumors from patients exhibiting a chemotherapy response, and TAFAZZIN mRNA expression was elevated in patients with no chemotherapy response. Hence, miR-125a-5p expression was negatively correlated with TAFAZZIN mRNA expression in breast cancer tissues. All these data suggested that miR-125a-5p reverses EMT and restores drug sensitivity by negatively regulating TAFAZZIN in breast cancer and, therefore, has potential as a novel therapeutic target for this disease.

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TGM2 knockdown reverses cisplatin chemoresistance in osteosarcoma

Cited by 23 publications

References 34 publications

Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways

Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways

Circular RNA circ_0081001 knockdown enhances methotrexate sensitivity in osteosarcoma cells by regulating miR-494-3p/TGM2 axis

miR‑125a‑5p reverses epithelial‑mesenchymal transition and restores drug sensitivity by negatively regulating TAFAZZIN signaling in breast cancer

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