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PAQR3 suppresses the growth of non-small cell lung cancer cells via modulation of EGFR-mediated autophagy.

ABSTRACT: Macroautophagy/autophagy is an evolutionarily conserved intracellular process that recycles and degrades intracellular components to sustain homeostasis in response to deficiency of nutrients or growth factors. PAQR3 is a newly discovered tumor suppressor that also regulates autophagy induced by nutrient starvation via AMPK and MTORC1 signaling pathways. In this study, we investigated whether PAQR3 modulates EGFR-mediated autophagy and whether such regulation is associated with the tumor suppressive activity of PAQR3. PAQR3 is able to inhibit the in vitro and in vivo growth of non-small cell lung cancer (NSCLC) cells. PAQR3 potentiates autophagy induced by EGFR inhibitor erlotinib. Knockdown of PAQR3 abrogates erlotinib-mediated reduction of BECN1 interaction with autophagy inhibitory proteins RUBCN/Rubicon and BCL2. PAQR3 blocks the interaction of BECN1 with the activated form of EGFR and inhibits tyrosine phosphorylation of BECN1. Furthermore, inhibition of autophagy by knocking down ATG7 abrogates the tumor suppressive activity of PAQR3 in NSCLC cells. Collectively, these data indicate that PAQR3 suppresses tumor progression of NSCLC cells through modulating EGFR-regulated autophagy.

Abbreviations

AKT: thymoma viral proto-oncogene; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; BCL2: B cell leukemia/lymphoma 2; BECN1: beclin 1; CCK-8: cell counting kit-8; CQ: chloroquine diphosphate; DMEM: Dulbecco's modified Eagle's medium; EdU: 5-ethynyl-2'-deoxyuridine; EGFR: epidermal growth factor receptor; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IgG: Immunoglobulin G; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: thiazolyl blue tetrazolium bromide; NSCLC: Non-small cell lung cancer; MAP2K/MEK: mitogen-activated protein kinase kinase; MAPK/ERK: mitogen-activated protein kinase; PAQR3: progestin and adipoQ receptor family member 3; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PRKAA/AMPK: protein kinase, AMP-activated alpha catalytic; RUBCN: rubicon autophagy regulator; RPS6: ribosomal protein S6; RAS: Ras proto-oncogene; RAF: Raf proto-oncogene; TKI: tyrosine kinase inhibitor; TUBA4A: tubulin alpha 4a; UVRAG: UV radiation resistance associated.

SUBMITTER: Cao Q

PROVIDER: S-EPMC7469495 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAnlotinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, has been widely used in advanced lung cancer patients, but the intrinsic mechanism of cancer cell elimination is not fully disclosed. In this study, we reported that anlotinib suppressed lung adenocarcinoma (LUAD) growth through inhibiting fatty acid synthase (FASN)-mediated lipid metabolism.MethodsTo investigate the underlying mechanisms of anlotinib, an A549 cell line-derived xenograft model was constructed and a proteomics technique was employed to screen potential markers. Gas chromatography-mass spectrometry (GC-MS) profiling of medium-long chain fatty acid and neutral lipid droplet fluorescence staining were employed to detect lipid metabolism in cancer cells. Subsequently, the effects of anlotinib on FASN expression were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. Short hairpin RNA (shRNA) knockdown of FASN was used to assess the role of FASN in the antitumor effect of anlotinib. A patient-derived xenograft (PDX) model was established to validate the efficacy of anlotinib in the patient and IHC staining of FASN was examined.ResultsOur data revealed that anlotinib significantly decreased the expression of proteins related to lipid metabolism. GC-MS profiling of medium-long chain fatty acid and neutral lipid droplet fluorescence staining validated that anlotinib could disturb the fatty acid metabolism in cancer cells, especially de novo lipogenesis. Mechanically, the messenger RNA (mRNA) and protein of FASN were down-regulated by anlotinib in A549 cells and FASN knockdown could diminish the antitumor effect of anlotinib in vitro. Remarkable tumor shrinkage by anlotinib was further shown in a patient with multiple-line treatment failure, and FASN reduction was evidenced in the corresponding patient-derived xenograft (PDX) model.ConclusionsAnlotinib could inhibit the growth of LUAD through FASN-mediated lipid metabolism. Our findings provide new insights into the antitumor mechanism of anlotinib in lung adenocarcinoma.

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PAQR3 suppresses the growth of non-small cell lung cancer cells via modulation of EGFR-mediated autophagy.

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