PI3K/Akt/mTOR signaling orchestrates the phenotypic transition and chemo-resistance of small cell lung cancer

Li, Xuefeng; Li, Cheng; Guo, Chenchen; Zhao, Qiqi; Cao, Jiayu; Huang, Hsin‐Yi; Yue, Meiting; Xue, Yun; Jin, Yujuan; Hu, Liang; Ji, Hongbin

doi:10.1016/j.jgg.2021.04.001

Cited by 27 publications

(16 citation statements)

References 45 publications

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“…For instance, the PI3K/Akt/mTOR pathway is play an important role in the resistant mechanism. This pathway is a favorable goal for the development of anti-cancer agents [48]. AKT expressions of the A549 and DMS 114 under the 25 µM ErPC3 was not changed while active form of Akt (p-Akt) was downregulated compared to the control group.…”

Section: Discussionmentioning

confidence: 96%

Antineoplastic Effects of Erufosine on Small and Non-Small Lung Cancer Cells Through Induction of Apoptosis and Cell Cycle Arrest

Abdik

2021

Preprint

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Background: Lung cancer (LC) is one of the most common types of cancer with a high mortality rate. Depending on molecular and histological properties, LC is divided into non–small-cell and small-cell lung cancer. Not only surgery but also radiotherapy, chemotherapy, or combination treatment are used for patients. However, the survival rate of LC is still very low. Erufosine (ErPC3) is a novel promising antineoplastic agent and inhibits the translocation of AKT to the plasma membrane by dephosphorylating AKT. Methods and Results: In the current study, the cell-type dependent effects of ErPC3 on cell viability, apoptotic situation, cell cycle distribution, related gene expression, and migration capacities of A549 and DMS 114 were investigated. As results, ErPC3 exhibited cytotoxic and pro-apoptotic properties against both cells, while DMS 114 was more affected. ErPC3 accumulated the cells in G2/M phase and blocked cell cycle. Proliferation markers were downregulated, while pro-apoptotic markers were upregulated in ErPC3 treated cells. Besides, ErPC3 displayed anti-migratory effect on A549 and DMS 114 compared to the control group according to scratch assay. Conclusion: These findings promise a treatment approach and drug development against LC. The obtained results from the recent study lead it necessary to carry out more detailed studies about ErPC3.

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Section: Discussionmentioning

confidence: 96%

Antineoplastic Effects of Erufosine on Small and Non-Small Lung Cancer Cells Through Induction of Apoptosis and Cell Cycle Arrest

Abdik

2021

Preprint

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“…In this study, we performed a microarray analysis of H69 cells and H69AR cells to obtain the DEGs and DELs. The DEGs and DEGs coexpressed with the top 10 DELs were both enriched in the Akt/mTOR pathway contributes to the chemoresistance of SCLC cells; however, this chemoresistance could be largely overcome by combining chemotherapy with PI3K/ Akt/mTOR pathway inhibitors (26). As a conserved serine/ threonine protein kinase, mTOR is a key gene for upstream pathways that regulate cell growth, proliferation, motility, survival, and autophagy (27).…”

Section: Discussionmentioning

confidence: 99%

“…Further, the PI3K/Akt/mTOR pathway has been shown to play an important role in the progression and metastasis of SCLC ( 25 ). The activation of the PI3K/Akt/mTOR pathway contributes to the chemoresistance of SCLC cells; however, this chemoresistance could be largely overcome by combining chemotherapy with PI3K/Akt/mTOR pathway inhibitors ( 26 ). As a conserved serine/threonine protein kinase, mTOR is a key gene for upstream pathways that regulate cell growth, proliferation, motility, survival, and autophagy ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of key genes and pathway related to chemoresistance of small cell lung cancer through an integrative bioinformatics analysis

Zeng¹,

Zhou²,

Zeng³

et al. 2022

Ann Transl Med

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Background: Small cell lung cancer (SCLC), the most malignant of all the lung cancer subtypes, is characterized by drug resistance. This study sought to explore the key genes and pathways associated with the chemoresistance of SCLC. Methods:The drug sensitivity of chemosensitive and chemoresistance SCLC cell lines was measured by Cell Counting Kit-8 assays. The total RNA from chemosensitive cell line H69 and chemoresistance cell line H69AR cells was extracted and subjected to messenger RNA (mRNA) and long non-coding RNA (lncRNA) microarray analyses. The differentially expressed genes (DEGs) and the differentially expressed lncRNAs (DELs) were screened out with a threshold of a |log fold change | ≥1 and an adjusted P value <0.05. A protein-protein interaction network was constructed, and hub genes were screened out. A lncRNA-mRNA co-expression network was also constructed. Gene Ontology and Kyoto Encyclopedia of Genes, Genomes enrichment analyses and Cis-regulatory element analyses were conducted on the DEGs and the top 10 upregulated DEL-co-expressed DEGs. The expression of the key genes was further analyzed in the GSE149507 data set and validated in H69/H69AR and H446/H446DDP cells by quantitative polymerase chain reaction assays. Results:The microarray results showed that a total of 609 mRNAs and 394 lncRNAs were differentially expressed in the chemoresistant SCLC cells. The mammalian target of rapamycin (mTOR) signaling pathway was enriched among the DEGs, the top 10 upregulated DEL-co-expressed DEGs, and the NCRNA00173-co-expressed DEGs, which included IGF1, INS, WNT6, WNT11, WNT2B, and SESN2. IGF1, WNT2B, and SESN2 were downregulated, and WNT11 was upregulated in the SCLC tumor tissues in the GSE149507 data set. Further, IGF1, WNT6, WNT11, and WNT2B were lowlier expressed and SESN2 and NCRNA00173 were more highly expressed in the chemoresistant cells than sensitive cells. Conclusions:The top 10 upregulated DELs containing NCRNA00173 may be involved in the regulation of drug resistance in SCLC. These DELs may regulate the genes related to the mTOR signaling pathway.These genes may also be biomarkers and potential targets for the treatment of SCLC.

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“…However, the mechanism of chemotherapy resistance in small cell lung cancer, which is characterized by many abnormalities in signaling pathways involving PIK3CA (PI3K/Protein kinase B [Akt]/the mammalian target of rapamycin [mTOR] pathway), may be informative. It has been reported that small cell lung cancer may be associated with chemotherapy resistance due to a phenotypic transition from suspension to an adhesion growth pattern caused by the activation of the PI3K/Akt/mTOR pathway [ 30 ]. PIK3CA mutation-positive PPC may have a similar mechanism.…”

Section: Discussionmentioning

confidence: 99%

PIK3CA mutations associated with a poor postoperative prognosis in patients with pulmonary pleomorphic carcinoma: a retrospective cohort study

et al. 2022

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Background Pulmonary pleomorphic carcinoma (PPC) is a rare type of non-small cell lung cancer characterized by high malignancy and a poor prognosis. PPC is associated with a high frequency of postoperative relapse, and shows resistance to chemotherapy. The high malignancy of cancers is associated with genomic instability, which is related to mutations of tumor suppressor genes, such as tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM). In addition, signaling pathways involving the oncogenes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and epidermal growth factor receptor (EGFR) are associated with resistance to chemotherapy. However, the association of PPC with these gene mutations remains unknown. We investigated the impact of TP53, ATM, PIK3CA, and EGFR mutations on the postoperative prognosis of PPC. Methods Fifty-five patients with PPC who underwent complete resection were studied. A gene mutation analysis was performed using next-generation sequencing. Postoperative overall survival of patients with gene mutations was evaluated using a multivariable Cox proportional hazards model in which the explanatory variables were the presence of each gene mutation, and the confounding factors were pathological stage and age. The robustness of the results was evaluated by a sensitivity analysis. Results The frequencies of pathogenic mutations in TP53, ATM, PIK3CA, and EGFR were 47, 0, 7, and 9%, respectively. A multivariable analysis adjusted for pathological stage and age showed a significant difference for only PIK3CA mutations. The hazard ratio (HR) for overall survival in cases with pathogenic mutations of PIK3CA for wild type or non-pathogenic mutations was 4.5 (95% confidence interval [CI] 1.1–18.8). Likewise, sensitivity analyses adjusted for pathological stage and sex (HR, 7.5; 95% CI 1.7–32.4) and for age and sex (HR, 5.4; 95% CI 1.4–21.7) resulted in similar findings. Although three patients with pathogenic mutations of PIK3CA that recurred postoperatively were treated by chemotherapy or immunotherapy, they survived for less than 2 years. Conclusions The postoperative prognosis of PPC with PIK3CA pathogenic mutations is particularly poor. Pathogenic mutations of PIK3CA may be a postoperative prognostic marker. Inhibition of signaling pathways associated with PIK3CA mutations may also be a target for chemotherapy after relapse of PPC.

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PI3K/Akt/mTOR signaling orchestrates the phenotypic transition and chemo-resistance of small cell lung cancer

Cited by 27 publications

References 45 publications

Antineoplastic Effects of Erufosine on Small and Non-Small Lung Cancer Cells Through Induction of Apoptosis and Cell Cycle Arrest

Antineoplastic Effects of Erufosine on Small and Non-Small Lung Cancer Cells Through Induction of Apoptosis and Cell Cycle Arrest

Identification of key genes and pathway related to chemoresistance of small cell lung cancer through an integrative bioinformatics analysis

PIK3CA mutations associated with a poor postoperative prognosis in patients with pulmonary pleomorphic carcinoma: a retrospective cohort study

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