ABCA6 affects the malignancy of Ewing sarcoma cells via cholesterol-guided inhibition of the IGF1R/AKT/MDM2 axis

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Michela Pasello1, Anna Maria Giudice2,3,4, Camilla Cristalli2

  • 1Experimental Oncology Laboratory, IRCCS Istituto Ortopedico Rizzoli, Bologna, 40136, Italy. michela.pasello@ior.it.

Cellular Oncology (Dordrecht, Netherlands)
|September 23, 2022
PubMed
Abstract

Insights

ATP-binding cassette (ABC) transporter ABCA6 acts as a tumor suppressor in Ewing sarcoma (EWS). Upregulated ABCA6 improves patient outcomes by reducing cell migration and enhancing chemotherapy response through cholesterol modulation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • ATP-binding cassette (ABC) transporters, particularly subfamily A (ABCA) members, are increasingly recognized as potential biomarkers in various cancers.
  • Their precise mechanisms of action, especially in pediatric malignancies like Ewing sarcoma (EWS), require further elucidation.
  • Ewing sarcoma presents significant unmet clinical challenges, highlighting the need for novel therapeutic targets and biomarkers.

Purpose of the Study:

  • To investigate the role of ABCA transporters in Ewing sarcoma (EWS).
  • To define the mechanistic basis of ABCA transporter function in EWS progression and treatment response.
  • To explore the potential of ABCA6 as a prognostic biomarker and therapeutic target in EWS.

Main Methods:

  • Quantitative reverse transcription PCR (RT-qPCR) to assess ABC transporter expression in localized EWS patient samples.
  • Statistical analysis (univariate and multivariate) of expression data against clinical outcomes in multiple datasets.
  • Gain- and loss-of-function studies in patient-derived xenograft (PDX) EWS cell lines.
  • Evaluation of intracellular cholesterol levels and the impact of cholesterol-lowering drugs on malignant parameters.

Main Results:

  • ABCA6, typically underexpressed in EWS, demonstrated a favorable prognostic significance when upregulated.
  • Increased ABCA6 expression correlated with reduced cell migration and enhanced chemosensitivity.
  • Mechanistically, ABCA6 diminished intracellular cholesterol, suppressed IGF1R/AKT/mTOR signaling, and promoted p53 activation, thereby enhancing doxorubicin's pro-apoptotic effects.
  • Simvastatin, a cholesterol-lowering drug, inhibited IGF1R/AKT/mTOR signaling and augmented doxorubicin efficacy.

Conclusions:

  • ABCA6 functions as a tumor suppressor in EWS by modulating cholesterol levels and inhibiting the IGF1R/AKT/MDM2 signaling pathway.
  • This mechanism enhances doxorubicin-induced apoptosis and reduces cancer cell migration.
  • ABCA6 shows promise as a biomarker for EWS progression and suggests the potential utility of statins as adjuvant therapy.
Keywords:
ABC family of transportersCholesterolEwing sarcomaStatinsTumor biomarkers

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