BCL2 induced by LAMTOR3/MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer

Kwon, Ok‐Seon; Hong, Soon-Ki; Kwon, Sophia; Go, Young-Hyun; Oh, Ensel; Cha, Hyuk‐Jin

doi:10.1016/j.canlet.2017.05.019

Cited by 26 publications

(41 citation statements)

References 45 publications

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“…Acquired resistance results in local tumor recurrence or failure of radiotherapy (6,7). Increasing evidence has demonstrated that epithelial-to-mesenchymal transition (EMT) mediated tumor metastasis is closely associated with radiation resistance (8,9). The biological process during EMT endows epithelial cells lose their apical-basal polarity and acquire mesenchymal cell traits (10,11), which is characterized by the loss of epithelial morphology and the acquisition of mesenchymal morphology, of which the epithelial markers includes E-cadherin, Desmoplakin, Occludins, Claudins, and ZO-1) and mesenchymalmarkers includs N-cadherin, vimentin, and FSP1.…”

Section: Introductionmentioning

confidence: 99%

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer

Tan

Wang

et al. 2020

Front. Oncol.

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Radiation therapy is a common and acceptable approach for lung cancer. Although the benefit of ionizing radiation (IR) is well-established, cancer cells can still survive via pro-survival and metastasis signaling pathways. Ras related C3 botulinum toxin substrate1 (RAC1), a member of Rho family GTPases, plays important roles in cell migration and survival. In the present study, we investigated the effects of RAC1 on the survival of lung cancer cells treated with irradiation. The results showed RAC1 is overexpressed in lung cancer cells and promoted cell proliferation and survival. Furthermore, IR induced RAC1 expression and activity via the activation of PI3K/AKT signaling pathway, and then enhancing cell proliferation, survival, migration and metastasis and increasing levels of epithelial-to-mesenchymal transition (EMT) markers, which facilitated the cell survival and invasive phenotypes. In addition, overexpression of RAC1 attenuated the efficacy of irradiation, while inhibition of RAC1 enhanced sensitivity of irradiation in xenograft tumors in vivo. Collectively, we further found that RAC1 enhanced radioresistance by promoting EMT via targeting the PAK1-LIMK1-Cofilins signaling in lung cancer. Our finding provides the evidences to explore RAC1 as a therapeutic target for radioresistant lung cancer cells.

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Section: Introductionmentioning

confidence: 99%

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer

Tan

Wang

et al. 2020

Front. Oncol.

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“…10,11 Upregulation of mesenchymal markers and reduction of epithelial markers were also observed in NSCLC specimens after chemoradiotherapy. 40 On the other hand, mesenchymal lung cancer cells were found to display increased radioresistance, 12 which suggested that EMT might in turn contribute to radioresistance in NSCLC. In our study, assessments of the radioresponse in miR-410 overexpression or knockdown cells demonstrated that miR-410 could increase radioresistance, as well as promote EMT, which also indicated that the occurrence of EMT was accompanied by radioresistance in NSCLC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a few studies have demonstrated that epithelial-mesenchymal transition (EMT) is positively associated with radioresistance in NSCLC. [10][11][12] However, most of these studies have mainly focused on radiation-induced changes in EMT characteristics. It remains unclear whether the occurrence of EMT can result in radioresistance in NSCLC, and little is known about whether the abnormal expression of genes or pathways can affect both EMT and radiosensitivity in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

miR-410 induces both epithelial–mesenchymal transition and radioresistance through activation of the PI3K/mTOR pathway in non-small cell lung cancer

Yue

Liao

et al. 2020

Sig Transduct Target Ther

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Radiotherapy remains one of the major treatments for non-small cell lung cancer (NSCLC) patients; whereas intrinsic or acquired radioresistance limits its efficacy. Nevertheless, most studies so far have only focused on acquired resistance. The exact mechanisms of intrinsic radioresistance in NSCLC are still unclear. A few studies have suggested that epithelial-mesenchymal transition (EMT) is associated with radioresistance in NSCLC. However, little is known about whether the abnormal expression of specific microRNAs induces both EMT and radioresistance. We previously found that miR-410 has multiple roles as an oncomiRNA in NSCLC. In this study, we revealed that miR-410 overexpression promoted EMT and radioresistance, accompanied by enhanced DNA damage repair both in vitro and in vivo. Conversely, knockdown of miR-410 showed the opposite effects. We further demonstrated that PTEN was a direct target of miR-410 by using bioinformatic tools and dual-luciferase reporter assays, and the miR-410-induced EMT and radioresistance were reversed by PI3K, Akt, and mTOR inhibitors or by restoring the expression of PTEN in NSCLC cells. In addition, we preliminarily found that the expression of miR-410 was positively correlated with EMT and negatively associated with the expression of PTEN in NSCLC specimens. In summary, these results demonstrated that miR-410 is an important regulator on enhancing both NSCLC EMT and radioresistance by targeting the PTEN/PI3K/mTOR axis. The findings suggest that miR-410-induced EMT might significantly contribute to the enhanced radioresistance. Therefore, miR-410 may serve as a potential biomarker or therapeutic target for NSCLC radiotherapy.

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“…cIAP1 and cIAP2 are members of the inhibitor of apoptosis proteins (IAPs) family, indirectly regulate apoptosis by preventing Smac for inhibiting XIAP-caspase interaction and by preventing the formation of caspase-8-activating platform. 25,26) Bcl-2 is one of the apoptotic protein markers, which regulated by nuclear factor κB or the cAMP-response elementbinding protein (CREB) transcription factor 27,28) . We speculate that ART might target the protein (s) of those pathway, which needs to be further verified.…”

Section: Discussionmentioning

confidence: 99%

Artemether Attenuates the Progression of Non-small Cell Lung Cancer by Inducing Apoptosis, Cell Cycle Arrest and Promoting Cellular Senescence

Chen

Huang

Tao

et al. 2019

Biological & Pharmaceutical Bulletin

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Lung cancer is the most common cause of cancer death, approximately 85% of which are non-small cell lung cancer (NSCLC). Here we found that artemether (ART), a natural derivative of artemisinin, significantly inhibits the proliferation of NSCLC cells in a dose-and time-dependent manner. We also demonstrated that high concentration of ART induces apoptosis in NSCLC cells through down-regulating the level of antiapoptotic protein B-cell lymphoma-2 (Bcl-2), cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2). While low concentration of ART inhibits the mRNA level of cell cycle related genes including cyclin-dependent kinase 1 (CDK1), cyclin-dependent kinase 2 (CDK2), cyclindependent kinase 6 (CDK6), cyclin A2, cyclin B1 and cyclin D1, leading to cell cycle arrest in NSCLC cells. Moreover, we confirmed that low concentration of ART induces DNA double-stranded breaks (DSBs), as well as promoting cellular senescence in NSCLC cells by up-regulating the mRNA and protein level of p16. Taken together, ART represents a promising new anti-NSCLC drug candidate that could attenuate progression of NSCLC cells in a p53-independent manner through inducing apoptosis, cell cycle arrest and promoting cellular senescence.

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BCL2 induced by LAMTOR3/MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer

Cited by 26 publications

References 45 publications

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer

miR-410 induces both epithelial–mesenchymal transition and radioresistance through activation of the PI3K/mTOR pathway in non-small cell lung cancer

Artemether Attenuates the Progression of Non-small Cell Lung Cancer by Inducing Apoptosis, Cell Cycle Arrest and Promoting Cellular Senescence

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