FGF2/FGFR1 regulates autophagy in FGFR1-amplified non-small cell lung cancer cells

Ye, Hong; Li, Ziming; Shao, Jiaxiang; Ji, Wei; Xia, Weiliang; Lü, Shun

doi:10.1186/s13046-017-0534-0

Cited by 54 publications

(42 citation statements)

References 55 publications

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“…Similarly, FGFR2 fusion genes that result in altered cell morphology and increased cell proliferation have been described in CCA [99]. It has been shown that FGFR alterations suppress autophagy, which could be associated with initial steps of carcinogenesis, and genetic or pharmacological FGFR inhibition in vitro induces protective autophagy in lung and breast cancer; therefore, inhibition of autophagy increases anticancer efficacy of FGFR inhibitors in these cells [100,101]. There are currently FGFR inhibitors in clinical development for CCA, opening the possibility of evaluating the combination of these inhibitors with autophagy modulators to increase efficacy.…”

Section: Cholangiocarcinoma Genetic and Epigenetic Alterations And Aumentioning

confidence: 95%

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Pérez‐Montoyo

2020

Cells

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Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumor microenvironment, but also to increase invasiveness and resistance to anticancer drugs such as chemotherapy. This review collects clinical evidence of autophagy deregulation during cholangiocarcinogenesis together with preclinical reports evaluating compounds that modulate autophagy to induce cholangiocarcinoma (CCA) cell death. Altogether, experimental data suggest an impairment of autophagy during initial steps of CCA development and increased expression of autophagy markers on established tumors and in invasive phenotypes. Preclinical efficacy of autophagy modulators promoting CCA cell death, reducing invasiveness capacity and resensitizing CCA cells to chemotherapy open novel therapeutic avenues to design more specific and efficient strategies to treat this aggressive cancer.

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Section: Cholangiocarcinoma Genetic and Epigenetic Alterations And Aumentioning

confidence: 95%

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Pérez‐Montoyo

2020

Cells

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“…Furthermore, consistent with our previous study, it was observed that PLCγ1 inhibition blocked mTOR and ULK1 phosphorylation in lung adenocarcinoma A549 cells, suggesting thereby that the suppression of PLCγ1/mTOR/ULK1 axis might contribute to PLCγ1 inhibition-driven autophagy. Activated ERK could regulate autophagy either positively or negatively [24][25][26]. Meanwhile, PLCγ1 regulation of ERK phosphorylation has been demonstrated previously [27,28].…”

Section: Discussionmentioning

confidence: 87%

Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro

Lü¹,

Fu²,

Chen³

et al. 2020

Int. J. Biol. Sci.

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Our previous studies indicated that phosphoinositide specific phospholipase Cγ1 (PLCγ1) was involved in autophagy induction in colon and hepatic carcinoma cells. However, whether and how PLCγ1 regulation in human lung adenocarcinoma is linked to autophagy remains unclear. Here, we assessed the protein expression of PLCγ1 in human lung adenocarcinoma tissue using immunohistochemistry assay and the relationship between PLCG1 and autophagy in The Cancer Genome Atlas Network (TCGA) using Spearman correlation analysis and GSEA software. Furthermore, the interaction between PLCγ1 and autophagy-related signal molecules was investigated in human lung adenocarcinoma A549 cells treated with different inhibitors or transduction with lentivirus-mediated PLCγ1 gene short-hairpin RNA (shRNA) vectors using MTT, clonogenicity, Transwell migration, RT-PCR, Caspase-3, mitochondrial transmembrane potential, and western blotting assays, as well as transmission electron microscope technique. Additionally, the effect of shRNA/PLCγ1 alone or combined with autophagic activator Lithium Chloride (LiCl) on tumor growth and metastasis was measured using immunohistochemistry and assays in A549 xenograft nude mouse model. The results showed that increased PLCγ1 expression occurred frequently in human lung adenocarcinoma tissue with higher grades of T in TNM staging classification. PLCγ1 significantly enriched in autophagic process and regulation, which negatively regulating autophagy was enriched in higher expression of PLCγ1. PLCγ1 inhibition partially reduced cell proliferation and migration of A549 cells, with an increased autophagic flux involving alterations of AMPKα, mTOR, and ERK levels. However, PLCγ1 inhibition-driven autophagy led to cell death without depending on Caspase-3 and RIP1. Additionally, the abrogation of PLCγ1 signaling by shRNA and combination with autophagic activator LiCl could efficaciously suppress tumor growth and metastasis in A549 xenograft nude mice, in combination with a decrease in P62 level. These findings collectively suggest that reduction of cell proliferation and migration by PLCγ1 inhibition could be partially attributed to PLCγ1 inhibition-driven autophagic cell death (ACD). It highlights the potential role of a combination between targeting PLCγ1 and autophagy pathway in anti-tumor therapy, which may be an efficacious new strategy to overcome the autophagy addition of tumor and acquired resistance to current therapy.

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“…Both Yuan et al . () and Chen et al . () found that blocking autophagy by knockdown of Beclin and ATG5 increased cell death by FGFR inhibition.…”

Section: Discussionmentioning

confidence: 96%

“…Autophagy has been previously reported in FGFR1‐amplified lung cancer models and a single breast cancer line following FGFR inhibition with AZD4547 (Yuan et al ., ) or PD166866, respectively (Chen et al ., ). In contrast to our findings in EC, FGFR inhibition in combination with either lysosomal protease inhibitors or chloroquine leads to a significant increase in lipidated LC3‐II or LC3 puncta in these lines, suggesting that FGFR inhibition increases autophagosome synthesis.…”

Section: Discussionmentioning

confidence: 97%

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Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

et al. 2019

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Endometrial cancer is the most commonly diagnosed gynaecological malignancy. Unfortunately, 15–20% of women demonstrate persistent or recurrent tumours that are refractory to current chemotherapies. We previously identified activating mutations in fibroblast growth factor receptor 2 ( FGFR 2) in 12% (stage I/ II ) to 17% (stage III / IV ) endometrioid EC s and found that these mutations are associated with shorter progression‐free and cancer‐specific survival. Although FGFR inhibitors are undergoing clinical trials for treatment of several cancer types, little is known about the mechanism by which they induce cell death. We show that treatment with BGJ 398, AZD 4547 and PD 173074 causes mitochondrial depolarization, cytochrome c release and impaired mitochondrial respiration in two FGFR 2‐mutant EC cell lines ( AN 3 CA and JHUEM 2). Despite this mitochondrial dysfunction, we were unable to detect caspase activation following FGFR inhibition; in addition, the pan‐caspase inhibitor Z‐ VAD ‐ FMK was unable to prevent cell death, suggesting that the cell death is caspase‐independent. Furthermore, while FGFR inhibition led to an increase in LC 3 puncta, treatment with bafilomycin did not further increase lipidated LC 3, suggesting that FGFR inhibition led to a block in autophagosome degradation. We confirmed that cell death is mitochondrial‐dependent as it can be blocked by overexpression of Bcl‐2 and/or Bcl‐ XL . Importantly, we show that combining FGFR inhibitors with the BH 3 mimetics ABT 737/ ABT 263 markedly increased cell death in vitro and is more effective than BGJ 398 alone in vivo , where it leads to marked tumour regression. This work may have implications for the design of clinical trials to treat a wide range of patients with FGFR ‐dependent malignancies.

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FGF2/FGFR1 regulates autophagy in FGFR1-amplified non-small cell lung cancer cells

Cited by 54 publications

References 55 publications

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro

Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

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