Dataset Information

FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1.

ABSTRACT: Fibroblast growth factor receptor-like 1 (FGFRL1), a member of the FGFR family, has been demonstrated to play important roles in various cancers. However, the role of FGFRL1 in small-cell lung cancer (SCLC) remains unclear. Our study aimed to investigate the role of FGFRL1 in chemoresistance of SCLC and elucidate the possible molecular mechanism. We found that FGFRL1 levels are significantly up-regulated in multidrug-resistant SCLC cells (H69AR and H446DDP) compared with the sensitive parental cells (H69 and H446). In addition, clinical samples showed that FGFRL1 was overexpressed in SCLC tissues, and high FGFRL1 expression was associated with the clinical stage, chemotherapy response and survival time of SCLC patients. Knockdown of FGFRL1 in chemoresistant SCLC cells increased chemosensitivity by increasing cell apoptosis and cell cycle arrest, whereas overexpression of FGFRL1 in chemosensitive SCLC cells produced the opposite results. Mechanistic investigations showed that FGFRL1 interacts with ENO1, and FGFRL1 was found to regulate the expression of ENO1 and its downstream signalling pathway (the PI3K/Akt pathway) in SCLC cells. In brief, our study demonstrated that FGFRL1 modulates chemoresistance of SCLC by regulating the ENO1-PI3K/Akt pathway. FGFRL1 may be a predictor and a potential therapeutic target for chemoresistance in SCLC.

SUBMITTER: Chen R

PROVIDER: S-EPMC7011138 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1.

Chen Rui R Li Deyu D Zheng Meng M Chen Bin B Wei Ting T Wang Yu Y Li Man M Huang Weimei W Tong Qin Q Wang Qi Q Zhu Yaru Y Fang Wei W Guo Linlang L Fang Shun S

Journal of cellular and molecular medicine 20200119 3

Fibroblast growth factor receptor-like 1 (FGFRL1), a member of the FGFR family, has been demonstrated to play important roles in various cancers. However, the role of FGFRL1 in small-cell lung cancer (SCLC) remains unclear. Our study aimed to investigate the role of FGFRL1 in chemoresistance of SCLC and elucidate the possible molecular mechanism. We found that FGFRL1 levels are significantly up-regulated in multidrug-resistant SCLC cells (H69AR and H446DDP) compared with the sensitive parental c ...[more]

PMID: 31957179

Similar Datasets

Project description:Glioblastoma (GBM) is the most common type of brain cancer and has the highest mortality. Dysregulated expression of wild‑type isocitrate dehydrogenase 1 (IDH1) has been demonstrated to promote the progression of primary GBM without accumulating D‑2‑hydroxyglutarate, which differs from IDH1 mutation‑related mechanisms of tumorigenesis. Previous studies have revealed several roles of wild‑type IDH1 in primary GBM, involving proliferation and apoptosis. However, the function of IDH1 in cell migration has not been investigated. In the current study, the results of bioinformatics analysis revealed that IDH1 expression was significantly upregulated in patients with primary GBM. Wound healing and Transwell assays demonstrated that IDH1 overexpression promoted cell migration in primary GBM cells and that IDH1 knockdown hindered this process. Furthermore, α‑ketoglutarate (α‑KG), which is the main product of IDH1‑catalyzed reactions, was significantly decreased by IDH1 knockdown and upregulated by IDH1 overexpression. α‑KG treatment significantly increased the migration of primary GBM cells. Additionally, RNA sequence analysis of patients with primary GBM reported significant alterations in the expression of phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway‑regulated genes, including Myc, Snail family transcriptional repressor 2 and Twist‑related protein 1, which are primarily cell migration regulatory factors. Western blotting revealed that the overexpression or knockdown of IDH1 promoted or inhibited the PI3K/AKT/mTOR pathway, respectively. α‑KG treatment of primary GBM cells also promoted the PI3K/AKT/mTOR pathway. Furthermore, IDH1‑overexpressing and α‑KG‑treated U87 cells were incubated with rapamycin, an mTOR‑specific inhibitor, and the results revealed that rapamycin treatment reversed the increased cell migration caused by IDH1 overexpression and α‑KG treatment. The results indicated that IDH1 regulated the migration of primary GBM cells by altering α‑KG levels and that the function of the IDH1/α‑KG axis may rely on PI3K/AKT/mTOR pathway regulation.

Project description:Breast cancer is the most prevalent type of cancer among women. Several types of drugs, targeting the specific proteins expressed on the breast cancer cell surface (such as receptor tyrosine kinases and immune checkpoint regulators) and proteins involved in cell cycle and motility (including cyclin-dependent kinases, DNA stabilisers, and cytoskeleton modulators) are approved for different subtypes of breast cancer. However, breast cancer also has a poor response to conventional chemotherapy due to intrinsic and acquired resistance, and an Akt fingerprint is detectable in most drug-resistant cases. Overactivation of Akt and its upstream and downstream regulators in resistant breast cancer cells is considered a major potential target for novel anti-cancer therapies, suggesting that Akt signalling acts as a cellular mechanism against chemotherapy. The present review has shown that sustained activation of Akt results in resistance to different types of chemotherapy. Akt signalling plays a cellular defence role against chemotherapy and (1) enhances multi-drug resistance, (2) increases reactive oxygen species at breast tumor microenvironment, (3) enhances anaerobic metabolism, (4) inhibits the tricarboxylic cycle, (5) promotes PD-L1 upregulation, (6) inhibits apoptosis, (7) increases glucose uptake, and more importantly (8) recruits and interconnects the plasma membrane, nucleus, endoplasmic reticulum, and mitochondria to hijack breast cancer cells and rescue these cells from chemotherapy. Therefore, Akt signalling is considered a cellular defence mechanism employed against chemotherapeutic effects. In addition, interfering roles of PI3K/Akt signalling on the current cytotoxic and molecularly targeted therapy as well as immunotherapy of breast cancer are discussed with a clinical approach. Although, alpelisib, a PIK3CA inhibitor, is the only PI3K/Akt pathway inhibitor approved for breast cancer, we also highlight well-evaluated inhibitors of PI3K/Akt signalling based on different subtypes of breast cancer, which are under clinical trials whether as monotherapy or in combination with other types of chemotherapy.

Dataset Information

FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1.

Publications

FGFRL1 affects chemoresistance of small-cell lung cancer by modulating the PI3K/Akt pathway via ENO1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets