ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs)

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• Receptor tyrosine kinase (RTK) pathways are crucial for glioblastoma (GBM) cell proliferation.
• Understanding RTK-inhibitor sensitivity is key for optimizing GBM treatment strategies.
• Activating transcription factor 4 (ATF4), a stress response gene, is implicated in cellular homeostasis but its role in GBM is unclear.

Purpose of the Study:

• To investigate the role of the ATF4/p-eIF2α pathway in glioblastoma stem cells (BTICs) treated with RTK inhibitors.
• To determine if ATF4 influences autophagy and proliferation in response to Sunitinib.
• To explore the therapeutic potential of targeting the ATF4 pathway in GBM.

Main Methods:

• Utilized primary tumor-initiating progenitor cell cultures (BTICs) from glioblastoma.
• Administered Sunitinib, a known RTK inhibitor, to BTIC cultures.
• Investigated the ATF4/p-eIF2α pathway activation and its effect on autophagy.
• Employed small interfering RNA (siRNA) to inhibit ATF4 expression.
• Assessed changes in autophagy and cell proliferation following ATF4 inhibition.

Main Results:

• The ATF4/p-eIF2α pathway was activated in BTICs upon Sunitinib treatment.
• RTK-inhibitor entrapment in lysosomes led to autophagosome accumulation.
• ATF4 upregulation further enhanced autophagy in Sunitinib-treated cells.
• ATF4 inhibition by siRNA reduced both autophagy and cell proliferation in a subset of BTIC cultures.

Conclusions:

• The ATF4/p-eIF2α pathway plays a pro-survival role in specific glioblastoma cell types under RTK inhibitor treatment.
• ATF4-mediated autophagy contributes to cell proliferation and survival in response to Sunitinib.
• Targeting ATF4 may offer a therapeutic strategy for a subset of glioblastoma patients, depending on cell type and treatment.