Proteasome inhibitors reduce CD73 expression partly via decreasing p-ERK in NSCLC cells

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Ecto-5'-nucleotidase (CD73) promotes tumor immunosuppression and is a target for anticancer drug development.
• Proteasome inhibitors are clinically used cancer therapeutics that impair protein degradation.

Purpose of the Study:

• To investigate the effect of proteasome inhibitors on CD73 expression in non-small cell lung cancer (NSCLC).
• To elucidate the role of the MAPK pathway in mediating the regulation of CD73 by proteasome inhibitors.
• To assess the impact of CD73 overexpression on the in vivo efficacy of proteasome inhibitors.

Main Methods:

• Treatment of NSCLC cell lines (NCI-H1299, others) with proteasome inhibitors and small-molecule drugs.
• Analysis of CD73, ERK, and p-ERK protein and mRNA levels using Western blotting and RT-qPCR.
• Investigation of the MAPK pathway using MEK and ERK inhibitors and fibroblast growth factor 2 (FGF2).
• Evaluation of CD73 overexpression effects in murine Lewis lung carcinoma (LLC) cells in vitro and in vivo, including Bortezomib treatment.

Main Results:

• Proteasome inhibitors consistently reduced both protein and mRNA levels of CD73 in NSCLC cells.
• The MAPK pathway, involving ERK and p-ERK, was implicated, as MEK and ERK inhibitors also lowered CD73 levels.
• FGF2 treatment partially rescued CD73 reduction, indicating pathway involvement.
• CD73 overexpression did not affect proteasome inhibitor efficacy in vitro but significantly reduced Bortezomib's in vivo anticancer activity.

Conclusions:

• Proteasome inhibitors decrease CD73 expression, potentially through modulation of the MAPK pathway.
• CD73 plays a critical role in the in vivo efficacy of proteasome inhibitors, particularly Bortezomib.
• These findings offer novel insights into the anticancer mechanisms of proteasome inhibitors and highlight CD73 as a potential factor influencing treatment response.