PAQR3 facilitates the ferroptosis of diffuse large B‐cell lymphoma via the regulation of LDLR‐mediated PI3K/AKT pathway

Abstract

Progesterone and adiponectin receptor 3 (PAQR3) has been found to regulate tumor progression by mediating cell ferroptosis. However, whether PAQR3 mediates ferroptosis in diffuse large B‐cell lymphoma (DLBCL) needs further investigation. The mRNA and protein levels of PAQR3 and low‐density lipoprotein receptor (LDLR) were assessed by qRT‐PCR and WB assays. Cell proliferation was detected by MTT assay and EdU assay. Shrunken mitochondria was counted under transmission electron microscope. Cell ferroptosis was evaluated by measuring the levels of malondialdehyde, reactive oxygen species, glutathione, Fe2+, and the protein expression of ferroptosis‐related markers. PAQR3 and LDLR interaction was confirmed by RIP assay and pull‐down assay. Our study showed that PAQR3 was underexpressed, while LDLR was overexpressed in DLBCL tissues and cells. Functionally, PAQR3 overexpression or LDLR knockdown restrained DLBCL cell proliferation and enhanced ferroptosis. Mechanistically, PAQR3 reduced LDLR expression by inhibiting its mRNA stability. Meanwhile, LDLR overexpression reversed PAQR3‐mediated the promoting on DLBCL cell ferroptosis, and LY294002 (PI3K/AKT inhibitor) eliminated the inhibiting effects of LDLR overexpression on DLBCL cell ferroptosis. Additionally, excessive PAQR3 reduced DLBCL tumor growth by enhancing tumor cell ferroptosis through LDLR‐mediated PI3K/AKT pathway. In conclusion, our data suggested that PAQR3 restrained DLBCL progression by aggravating ferroptosis, which was achieved by inhibiting LDLR expression to repress PI3K/AKT pathway.

Regulation of ferroptosis by PI3K/Akt signaling pathway: a promising therapeutic axis in cancer

“…In vivo , OE-PAQR3 suppresses DLBCL tumor growth and enhances ferroptosis, while OE-LDLR counters these effects. These findings reveal a mechanism where PAQR3 modulates ferroptosis through LDLR/PI3K/AKT, suggesting a potential therapeutic target in DLBCL ( Song et al, 2023 ).…”

Metabolism-regulated ferroptosis in cancer progression and therapy

“…Low-density lipoprotein receptor (LDLR) is essential for maintaining cholesterol homeostasis, which sensitize cancer cells to ferroptosis through inhibition of GPX4 via mediating cholesterol uptake [154]. Furthermore, a recent study by Zhong et al demonstrated that inhibition of LDLR can promote ferroptosis through the PI3K/AKT pathway in diffuse large B-cell lymphoma (DLBCL) [156].…”