SOX9 promotes epidermal growth factor receptor-tyrosine kinase inhibitor resistance via targeting β-catenin and epithelial to mesenchymal transition in lung cancer

Tripathi, Surya Kant; Biswal, Bijesh K.

doi:10.1016/j.lfs.2021.119608

Cited by 12 publications

(10 citation statements)

References 45 publications

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“…Our previous report also suggests that SOX9 is highly expressed in NSCLC, and silencing of SOX9 inhibited the NSCLC cell proliferation 21 . In this study, depletion of SOX9 and EVO treatment showed similar results; these indicate that EVO may inhibit lung cancer cell proliferation by regulating SOX9.…”

Section: Discussionsupporting

confidence: 82%

“…We have previously shown that SOX9 is involved in cell proliferation, invasion, migration, and stem cell renewal in NSCLC cell lines 21 . In this study, we have found that EVO inhibits stemness in cancer cells.…”

Section: Resultssupporting

confidence: 53%

“…We have previously shown that SOX9 is involved in cell proliferation, invasion, migration, and stem cell renewal in NSCLC cell lines. 21 In this study, we have found that EVO inhibits stemness in cancer cells. Therefore, to know the molecular players involved in stemness, we have checked the expression of SOX9 in response to EVO in NSCLC cells.…”

Section: Sox9 and β-Catenin Are Pivotal Cellular Targets Of Evo In Ns...mentioning

confidence: 71%

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Evodiamine inhibits stemness and metastasis by altering the SOX9–β‐catenin axis in non‐small‐cell lung cancer

Panda

Biswal

2022

J of Cellular Biochemistry

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Evodiamine (EVO), a natural dietary alkaloid extracted from the roots of the Evodia rutaecarpa, has shown anticancer activities. Here, we have investigated EVO's role in inhibiting cell proliferation and migration in A549 and NCI‐H522 lung cancer cells. EVO decreased the cell viability in A549 and NCI‐H522 cells in a dose‐ and time‐dependent manner. It also induced apoptosis by downregulating the expression of antiapoptotic Bcl‐2 and upregulating the expression of cleaved caspase‐3 and PARP. In addition, the treatment of EVO elevated the level of reactive oxygen species (ROS) generation inside the cells to induce the cell death pathways. In contrast, the pretreatment of ROS scavenger, N‐acetyl cysteine, reverses the effect of EVO and attenuates cell death. Moreover, excess ROS generation in response to EVO resulted in the depletion of mitochondrial membrane potential. Furthermore, it induced DNA damage and arrested the cell cycle at the G2/M phase in A549 and NCI‐H522 cells. Our study also investigated that EVO significantly suppressed tumorigenicity by inhibiting colony formation and tumorsphere formation. However, the treatment of EVO downregulated the cancer stem cell markers CD44 and CD133 in non‐small‐cell lung cancer. The inhibitory effect of EVO on cell invasion was mediated by altering the expression of E‐cadherin, ZO‐1, N‐cadherin, and Vimentin. Additionally, we have revealed that EVO treatment showed downregulation of SOX9, an upstream component of β‐catenin. Lastly, we have demonstrated that EVO targets the SOX9–β‐catenin axis by reducing SOX9 and β‐catenin expression. These findings suggested that EVO could be a promising agent for treating human lung cancer.

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Section: Discussionsupporting

confidence: 82%

Section: Resultssupporting

confidence: 53%

Section: Sox9 and β-Catenin Are Pivotal Cellular Targets Of Evo In Ns...mentioning

confidence: 71%

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Evodiamine inhibits stemness and metastasis by altering the SOX9–β‐catenin axis in non‐small‐cell lung cancer

Panda

Biswal

2022

J of Cellular Biochemistry

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“…Epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors have been used to treat NSCLC, although resistance to them typically develops after 10 months. It was shown using the spheroid model that the acquisition of resistance to EGFR inhibitor gefitinib is mediated by the induction of transcription factor Sox9, which contributes to β-catenin overexpression and EMT ( 50 ). Another study reports that treatment of patient-derived NSCLC spheroids with erlotinib leads to a change in clonal composition of the spheroids, resulting in the outgrowth of erlotinib-resistant subpopulations ( 38 ).…”

Section: Study Of Cancer Cell Signaling In Nsclc Spheroidsmentioning

confidence: 99%

Biomedical Applications of Non-Small Cell Lung Cancer Spheroids

et al. 2021

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Lung malignancies accounted for 11% of cancers worldwide in 2020 and remained the leading cause of cancer deaths. About 80% of lung cancers belong to non-small cell lung cancer (NSCLC), which is characterized by extremely high clonal and morphological heterogeneity of tumors and development of multidrug resistance. The improvement of current therapeutic strategies includes several directions. First, increasing knowledge in cancer biology results in better understanding of the mechanisms underlying malignant transformation, alterations in signal transduction, and crosstalk between cancer cells and the tumor microenvironment, including immune cells. In turn, it leads to the discovery of important molecular targets in cancer development, which might be affected pharmaceutically. The second direction focuses on the screening of novel drug candidates, synthetic or from natural sources. Finally, “personalization” of a therapeutic strategy enables maximal damage to the tumor of a patient. The personalization of treatment can be based on the drug screening performed using patient-derived tumor xenografts or in vitro patient-derived cell models. 3D multicellular cancer spheroids, generated from cancer cell lines or tumor-isolated cells, seem to be a helpful tool for the improvement of current NSCLC therapies. Spheroids are used as a tumor-mimicking in vitro model for screening of novel drugs, analysis of intercellular interactions, and oncogenic cell signaling. Moreover, several studies with tumor-derived spheroids suggest this model for the choice of “personalized” therapy. Here we aim to give an overview of the different applications of NSCLC spheroids and discuss the potential contribution of the spheroid model to the development of anticancer strategies.

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“…Recent evidence suggests that SOX9 is associated with clinical tumor-node-metastasis stage and it can stimulate the malignant biological characteristics of NSCLC in vitro [ 15 ]. Meanwhile, upregulated SOX9 can enhance gefitinib resistance of lung cancer, corresponding to increased cancer cell oncogenic phenotypes and gefitinib intake [ 16 ]. SOX9 is a transcriptional mediator of SPP1 in hepatocytes where SOX9 can activate the expression of SPP1 [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Deubiquitylase OTUD1 confers Erlotinib sensitivity in non-small cell lung cancer through inhibition of nuclear translocation of YAP1

Liu

Zhong

et al. 2022

Cell Death Discov.

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Evidence exists suggesting tumor-inhibiting properties of deubiquitylase OTUD1 in various malignancies. We herein investigated the anti-tumor effect and clarified the downstream mechanisms of OTUD1 in the chemoresistance of non-small cell lung cancer (NSCLC) cells. Expression of OTUD1 was examined in NSCLC (PC-9 cells) and erlotinib-resistant NSCLC (PC-9/ER) cell lines. OTUD1 was bioinformatically predicted to be weakly expressed in NSCLC tissue samples and verified in PC-9/ER cells. PC-9/ER cells were subsequently subjected to ectopic expression of OTUD1 alone or combined with SOX9 to dissect out the effect of OTUD1 on the proliferation, chemoresistance and apoptosis in vitro and in vivo. OTUD1 upregulation sensitized NSCLC cells to erlotinib both in vitro and in vivo. In the presence of OTUD1 overexpression, nuclear translocation of YAP1 was inhibited and its expression was inactivated. This effect of OTUD1 was associated with the decreased ubiquitination level of YAP1. SOX9/SPP1 inactivation was the consequence of inhibited nuclear translocation of YAP1. Overexpression of SOX9 reversed the inhibitory effect of OTUD1 on the resistance of NSCLC cells to erlotinib. In conclusion, our study reveals that OTUD1 potentially acts as a tumor suppressor and suppresses erlotinib resistance of NSCLC through the YAP1/SOX9/SPP1 axis, suggesting that OTUD1 may serve as a target for reducing chemoresistance for NSCLC.

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SOX9 promotes epidermal growth factor receptor-tyrosine kinase inhibitor resistance via targeting β-catenin and epithelial to mesenchymal transition in lung cancer

Cited by 12 publications

References 45 publications

Evodiamine inhibits stemness and metastasis by altering the SOX9–β‐catenin axis in non‐small‐cell lung cancer

Evodiamine inhibits stemness and metastasis by altering the SOX9–β‐catenin axis in non‐small‐cell lung cancer

Biomedical Applications of Non-Small Cell Lung Cancer Spheroids

Deubiquitylase OTUD1 confers Erlotinib sensitivity in non-small cell lung cancer through inhibition of nuclear translocation of YAP1

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