PAQR3 inhibits proliferation and aggravates ferroptosis in acute lymphoblastic leukemia through modulation Nrf2 stability

Abstract

Introduction Acute lymphoblastic leukemia (ALL) is a usual hematological tumor, which was featured by malignant proliferation of lymphoid progenitor cells. Many important factors participate into the regulation of ALL, including proteins. PAQR3 (also named RKTG) has been proved to take part in many human cancers by acting as a tumor suppressor. PAQR3 has bee n shown to repress human leukemia cells proliferation and induce cell apoptosis, but its role and relevant regulatory mechanism on cell proliferation and ferroptosis in ALL needs more exploration. Methods The genes expression was detected through quantitative reverse transcription polymerase chain reaction (mRNA) or western blot (protein). The cell proliferation was assessed through Cell Counting Kit‐8 and 5‐ethynyl‐2‐deoxyuridine assays. The levels of MDA, DCF, and intracellular free Fe in ALL cells were tested through the commercial kits. The cell apoptosis was determined through flow cytometry analysis. The binding ability of PAQR3 and nuclear factor erythroid 2‐related factor 2 (Nrf2) was verified through pull down assay. Results PAQR3 expression was firstly assessed in ALL patients and cell lines, and discovered to be downregulated. It was verified that PAQR3 suppressed ALL cells proliferation. Further experiments proved that PAQR3 aggravates ferroptosis in ALL. In addition, AQR3 bound with Nrf2, and modulated its expression through ubiquitination in ALL. Finally, through rescue assays, it was demonstrated that Nrf2 overexpression reversed the effects of PAQR3 on cell proliferation and ferroptosis. Conclusion Findings from our work uncovered that PAQR3 inhibited proliferation and aggravated ferroptosis in ALL through modulation Nrf2 stability. This study suggested that PAQR3 may serve as an effective biological marker for ALL treatment.

Molecular Mechanisms of Ferroptosis and Updates of Ferroptosis Studies in Cancers and Leukemia

“…They revealed that autophagy-mediated upregulation of voltage-dependent anion channel 3 (VDAC3) promotes ferroptosis and that the activation of autophagy by rapamycin exerts synergistic anti-leukemia effects with erastin in vivo. Another study demonstrates that progestin and adipoQ receptor 3 (PAQR3) enhances erastin- as well as RSL3-induced ferroptosis in ALLcells through the degradation of NRF2 [ 206 ]. Recently, an extensive whole-genome CRISPR knockout screen of 7 B-ALL cell lines revealed system x c − —GSH—GPX4 axis to be a common therapeutic vulnerability in B-ALL, which is partially attributed to low levels of GSH and FSP1 in these cells [ 187 ].…”

Ferroptosis in Leukemia: Lessons and Challenges

“…However, relapse occurred in patients ranging from 25% to 35% [47]. Interestingly, ferroptosis is suggested to be a promising strategy for cancer treatment and therefore should also be evaluated in ALL [48,49].…”

“…PAQR3 (also known as RKTG) has been proved to take part in many human cancers by acting as a tumor suppressor. Jin and Tong [48] showed PAQR3 inhibited proliferation and aggravated ferroptosis in ALL through modulation of Nrf2 stability. This study suggested that PAQR3 may serve as an effective biological marker for ALL treatment.…”

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

“…4 For example, overexpressed PAQR3 restrained esophageal cancer cell proliferation and metastasis, 5 and PAQR3 played an anti-tumor role in acute lymphoblastic leukemia by promoting cell ferroptosis. 6 However, it is not clear whether PAQR3 regulates ferroptosis in DLBCL.…”

“…Progesterone and adiponectin receptor 3 (PAQR3) is a member of PAQR family of transmembrane proteins 3 and has been considered as a tumor suppressor to mediate tumor progression 4 . For example, overexpressed PAQR3 restrained esophageal cancer cell proliferation and metastasis, 5 and PAQR3 played an anti‐tumor role in acute lymphoblastic leukemia by promoting cell ferroptosis 6 . However, it is not clear whether PAQR3 regulates ferroptosis in DLBCL.…”