Some patients with activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) remain resistant to the CHOP (cyclophosphamide, vincristine, doxorubicin [DOX], and prednisone) and rituximab (R)-CHOP treatment regimens. DOX induces reactive oxygen species (ROS) accumulation in ABC-DLBCL. Pyruvate kinase 2 (PKM2) is a crucial enzyme in glycolysis and plays metabolic and non-metabolic functions in tumor development. However, the role of PKM2 in modulating DOX sensitivity in ABC-DLBCL is unclear. In this study, PKM gene was highly expressed in common databases, and high PKM expression predicts poor prognosis. Inhibiting PKM2 increased DOX chemosensitivity and assisted DOX to induce cell apoptosis and cell cycle arrest. In the metabolic function of PKM2, inhibiting and knocking down PKM2 assisted DOX to inhibit glycolysis, disrupted the glutathione (GSH)/ROS balance, and activated oxidative stress-related pathways. Supplementation with GSH-MEE ameliorated ROS accumulation and apoptosis caused by DOX/PKM2i treatment. In the non-metabolic function of PKM2, inhibiting PKM2 caused DOX-induced NF-κB signaling pathway suppression. The histone acetyltransferases and deacetylases inhibitor chidamide functioned concurrently with DOX to inhibit cell viability and decreased PKM2 expression. In conclusion, this study revealed that enhanced DOX chemosensitivity can be achieved by inhibiting the metabolic and non-metabolic functions of PKM2 and partly elucidated the anti-tumor mechanism of chidamide.

Key Words:

DLBCL; PKM2; DOX; glycolysis; GSH/ROS; NF-κB; chidamide

Disclosures

No relevant conflicts of interest to declare.

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2024
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