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Inhibition of SMYD2 Sensitized Cisplatin to Resistant Cells in NSCLC Through Activating p53 Pathway.

ABSTRACT: The protein lysine methyltransferase SMYD2 has recently emerged as a new enzyme modulate gene transcription or signaling pathways, and involved into tumor progression. However, the role of SMYD2 in drug resistant is still not known. Here, we found that inhibition of SMYD2 by specific inhibitor could enhance the cell sensitivity to cisplatin (CDDP), but not paclitaxel, NVB, and VCR in non-small cell lung cancer (NSCLC). Further study showed that SMYD2 and its substrates were overexpressed in NSCLC resistant cells, and the inhibition of SMYD2 or knockdown by specific siRNA could reverse the cell resistance to cisplatin treatment in NSCLC/CDDP cells. In addition, our data indicated that the inhibition or knockdown SMYD2 inhibit tumor sphere formation and reduce cell migration in NSCLC/CDDP cells, but not in NSCLC parental cells. Mechanistically, inhibition of SMYD2 could enhance p53 pathway activity and induce cell apoptosis through regulating its target genes, including p21, GADD45, and Bax. On the contrary, the sensitivity of cells to cisplatin was decreased after knockdown p53 or in p53 deletion NSCLC cells. The synergistically action was further confirmed by in vivo experiments. Taken together, our results demonstrate SMYD2 is involved into cisplatin resistance through regulating p53 pathway, and might become a promising therapeutic target for cisplatin resistance in NSCLC.

SUBMITTER: Shang L

PROVIDER: S-EPMC6498871 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Inhibition of SMYD2 Sensitized Cisplatin to Resistant Cells in NSCLC Through Activating p53 Pathway.

Shang Lei L Wei Minjie M

Frontiers in oncology 20190426

The protein lysine methyltransferase SMYD2 has recently emerged as a new enzyme modulate gene transcription or signaling pathways, and involved into tumor progression. However, the role of SMYD2 in drug resistant is still not known. Here, we found that inhibition of SMYD2 by specific inhibitor could enhance the cell sensitivity to cisplatin (CDDP), but not paclitaxel, NVB, and VCR in non-small cell lung cancer (NSCLC). Further study showed that SMYD2 and its substrates were overexpressed in NSCL ...[more]

PMID: 31106145

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Project description:Hypoxia is commonly observed in solid tumors and contributes to the resistance of DNA damage drugs. However, the mechanisms behind this resistance are still unclear. In this study, we aimed to explore the effects of hypoxia-induced exosomes on non-small cell lung cancer (NSCLC). Methods: NSCLC cells were subjected to either normoxic or hypoxic conditions to assess cell survival and changes in the expression levels of key proteins. Comparative proteomics were performed to identify exosomal PKM2 in normoxic or hypoxic cisplatin-resistant NSCLC cells-derived exosomes. Functions of hypoxia induced-exosomal PKM2 in promoting cisplatin resistance to NSCLC cells were evaluated both in vitro and in vivo experiments and the molecular mechanisms of hypoxia induced-exosomal PKM2 were demonstrated using flow cytometry, immunoblotting, oxidative stress detection and histological examination. A series of in vitro experiments were performed to evaluate the function of hypoxia-induced exosomes on cancer-associated fibroblasts (CAFs). Results: Hypoxia exacerbated the cisplatin resistance in lung cancer cells due to the increased expression of PKM2 that was observed in the exosomes secreted by hypoxic cisplatin-resistance cells. We identified that hypoxia-induced exosomal PKM2 transmitted cisplatin-resistance to sensitive NSCLC cells in vitro and in vivo. Mechanistically, hypoxia-induced exosomal PKM2 promoted glycolysis in NSCLC cells to produce reductive metabolites, which may neutralize reactive oxygen species (ROS) induced by cisplatin. Additionally, hypoxia-induced exosomal PKM2 inhibited apoptosis in a PKM2-BCL2-dependent manner. Moreover, hypoxia-induced exosomal PKM2 reprogrammed CAFs to create an acidic microenvironment promoting NSCLC cells proliferation and cisplatin resistance. Conclusions: Our findings revealed that hypoxia-induced exosomes transmit cisplatin resistance to sensitive NSCLC cells by delivering PKM2. Exosomal PKM2 may serve as a promising biomarker and therapeutic target for cisplatin resistance in NSCLC.

Project description:BackgroundThe cisplatin-resistance is still a main course for chemotherapy failure of lung cancer patients. Cisplatin-resistant cancer cells own higher malignance and exhibited increased metastatic ability, but the mechanism is not clear. In this study, we investigated the effects of Ataxia Telangiectasia Mutated (ATM) on lung cancer metastasis.Materials and methodsCisplatin-resistant A549CisR and H157CisR cell line were generated by long-term treating parental A549 and H157 cells (A549P and H157P) with cisplatin. Cell growth, cell migration and cell invasion were determined. Gene expressions were determined by Western Blot and qPCR. Tumor metastasis was investigated using a xenograft mouse model.ResultsThe IC50 of the cisplatin-resistant cells (A549CisR and H157CisR cells) to cisplatin was 6-8 higher than parental cells. The A549CisR and H157CisR cells expressed lower level of E-cadherin and higher levels of N-cadherin, Vimentin and Snail compared to the parental A549P and H157P cells, and exhibited stronger capabilities of metastatic potential compared to the parental cells. The ATM expression was upregulated in A549CisR and H157CisR cells and cisplatin treatment also upregulated expression of ATM in parental cells, The inhibition of ATM by using specific ATM inhibitor CP466722 or knock-down ATM by siRNA suppressed Epithelial-to-Mesenchymal transition (EMT) and metastatic potential of A549CisR and H157CisR cells. These data suggest that ATM mediates the cisplatin-resistance in lung cancer cells. Expressions of JAK1,2,、 STAT3 、PD-L1 and ATM were increased in A549CisR and H157CisR cells and could by induced by cisplatin in parental lung cancer cells. Interestedly, ATM upregulated PD-L1 expression via JAK1,2/STAT3 pathway and inhibition of ATM decreased JAK/STAT3 signaling and decreased PD-L1 expression. The treatment of PD-L1 neutralizing Ab reduced EMT and cell invasion. Inhibition of JAK1,2/STAT3 signaling by specific inhibitors suppressed ATM-induced PD-L1 expression, EMT and cell invasion. Importantly, inhibition of ATM suppressed EMT and tumor metastasis in cisplatin-resistant lung cancer cells in an orthotopic xenograft mouse model.ConclusionsOur results show that ATM regulates PD-L1 expression through activation of JAK/STAT3 signaling in cisplatin-resistant cells. Overexpression of ATM contributes to cisplatin-resistance in lung cancer cells. Inhibition of ATM reversed EMT and inhibited cell invasion and tumor metastasis. Thus, ATM may be a potential target for the treatment of cisplatin-resistant lung cancer.

Dataset Information

Inhibition of SMYD2 Sensitized Cisplatin to Resistant Cells in NSCLC Through Activating p53 Pathway.

Publications

Inhibition of SMYD2 Sensitized Cisplatin to Resistant Cells in NSCLC Through Activating p53 Pathway.

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