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Knockdown of NADK promotes LUAD ferroptosis via NADPH/FSP1 axis
Xiangpeng Meng1, Fang Peng2, Shijie Yu1
1Liaoning Key Laboratory of Proteomics, Dalian Medical University, Dalian, 116044, China.
Background:
Lung cancer is a serious threat to human health and is the first leading cause of cancer death. Ferroptosis, a newly discovered form of programmed cell death associated with redox homeostasis, is of particular interest in the lung cancer, given the high oxygen environment of lung cancer. NADPH has reducing properties and therefore holds the potential to resist ferroptosis. Resistance to ferroptosis exists in lung cancer, but the role of NADK in regulating ferroptosis in lung cancer has not been reported yet.
Methods:
Immunohistochemistry (IHC) was used to analyse the expression of NADK in 86 cases of lung adenocarcinoma(LUAD) and adjacent tissues, and a IHC score was assigned to each sample. Chi-square and kaplan-meier curve was performed to analyse the differences in metastasis and five-year survival between the two groups with NADK high or low scores. Proliferation of NADK-knockdown LUAD cell lines was detected in vivo and vitro. Furthermore, leves of ROS, MDA and Fe2+ were measured to validate the effect and mechanism of NADK on ferroptosis in LUAD.
Results:
The expression of NADK was significantly evaluated in LUAD tissues as compared to adjacent non-cancerous tissues. The proliferation of NADK-knockdown cells was inhibited both in vivo and vitro, and increasing levels of intracellular ROS, Fe2+ and lipid peroxide products (MDA) were observed. Furthermore, NADK-knockdown promoted the ferroptosis of LUAD cells induced by Erastin/RSL3 by regulating the level of NADPH and the expression of FSP1. Knockdown of NADK enhanced the sensitivities of LUAD cells to Erastin/RSL3-induced ferroptosis by regulating NADPH level and FSP1 expression.
Conclusions:
NADK is over-expressed in LUAD patients. Knockdown of NADK inhibited the proliferation of LUAD cells both in vitro and in vivo and promotes the Erastin/RSL3-induced ferroptosis of LUAD cells by down-regulating the NADPH/FSP1 axis.
Insights
Nicotinamide adenine dinucleotide phosphate (NADPH) kinase (NADK) is overexpressed in lung adenocarcinoma (LUAD). Knocking down NADK inhibits LUAD cell proliferation and promotes ferroptosis by regulating the NADPH/FSP1 axis.
Area of Science:
- Oncology
- Cell Death Research
- Biochemistry
Background:
- Lung cancer remains a leading cause of cancer mortality.
- Ferroptosis, a form of programmed cell death, is relevant to lung cancer due to its high oxygen environment.
- NADPH's reducing properties suggest a role in resisting ferroptosis, but NADK's function in lung cancer ferroptosis is unknown.
Purpose of the Study:
- To investigate the role of NADK in regulating ferroptosis in lung adenocarcinoma (LUAD).
- To determine if NADK expression correlates with LUAD progression and patient survival.
- To elucidate the molecular mechanisms by which NADK influences ferroptosis in LUAD.
Main Methods:
- Immunohistochemistry (IHC) to assess NADK expression in 86 LUAD tissues and adjacent controls.
- In vivo and in vitro proliferation assays of NADK-knockdown LUAD cell lines.
- Measurement of reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ levels to assess ferroptosis.
- Analysis of NADPH levels and FSP1 expression.
Main Results:
- NADK expression was significantly elevated in LUAD tissues compared to adjacent tissues.
- NADK knockdown inhibited LUAD cell proliferation in vitro and in vivo.
- Knockdown of NADK increased intracellular ROS, Fe2+, and MDA levels, indicating enhanced ferroptosis.
- NADK knockdown promoted Erastin/RSL3-induced ferroptosis by down-regulating NADPH and FSP1 expression.
Conclusions:
- NADK is overexpressed in LUAD patients.
- NADK knockdown inhibits LUAD cell proliferation and enhances ferroptosis.
- The NADPH/FSP1 axis is a key mechanism regulated by NADK in LUAD ferroptosis.
