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D-galactose induces necroptotic cell death in neuroblastoma cell lines
1Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, #1 Keyuan 4 Road, Gaopeng Avenue, High-tech Zone, Chengdu 610041, People's Republic of China.
Abstract:
D-Galactose (D-gal) can induce oxidative stress in non-cancer cells and result in cell damage by disturbing glucose metabolism. However, the effect of D-gal on cancer cells is yet to be explored. In this study, we investigated the toxicity of D-gal to malignant cells specifically neuroblastoma cells. As the results, high concentrations of D-gal had significant toxicity to cancer cells, whereas the same concentrations of glucose had no; the viability loss via D-gal treatment was prominent to malignant cells (Neuro2a, SH-SY5Y, PC-3, and HepG2) comparing to non-malignant cells (NIH3T3 and LO(2)). Differing from the apoptosis induced by H(2) O(2), D-gal damaged cells showed the characters of necrotic cell death, such as trypan blue-tangible and early phase LDH leakage. Further experiments displayed that the toxic effect of D-gal can be alleviated by necroptosis inhibitor Necrostatin (Nec-1) and autophagy inhibitor 3-methyladenine (3-MA) but not by caspase inhibitor z-VAD-fmk. D-Gal treatment can transcriptionally up-regulate the genes relevant to necroptosis (Bmf, Bnip3) and autophagy (Atg5, TIGAR) but not the genes related to apoptosis (Caspase3, Bax, and p53). D-Gal did not activate Caspase-3, but prompted puncta-like GFP-LC3 distribution, an indicator for activated autophagy. The involvement of aldose reductase (AR)-mediated polyol pathway was proved because the inhibitor of AR can attenuate the toxicity of D-gal and D-gal treatment elevates the expression of AR. This study demonstrates for the first time that D-gal can induce non-apoptotic but necroptotic cell death in neuroblastoma cells and provides a new clue for developing the strategy against apoptosis-resistant cancers.
Insights
D-galactose demonstrates significant toxicity to cancer cells, inducing necroptotic cell death via the polyol pathway. This offers a novel strategy against apoptosis-resistant cancers.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- D-galactose (D-gal) induces oxidative stress and damage in non-cancer cells by disrupting glucose metabolism.
- The effects of D-gal on cancer cells, particularly neuroblastoma, remain largely unexplored.
Purpose of the Study:
- To investigate the toxicity of D-gal on malignant neuroblastoma cells.
- To elucidate the mechanism of D-gal-induced cell death in cancer.
Main Methods:
- Assessing D-gal toxicity in various cancer and non-malignant cell lines.
- Analyzing cell death markers (trypan blue, LDH leakage) and gene expression.
- Utilizing inhibitors for necroptosis, autophagy, and apoptosis.
- Investigating the role of the aldose reductase (AR)-mediated polyol pathway.
Main Results:
- High D-gal concentrations exhibited significant toxicity to cancer cells (Neuro2a, SH-SY5Y, PC-3, HepG2) but not non-malignant cells (NIH3T3, LO(2)).
- D-gal induced necrotic cell death, characterized by trypan blue uptake and early LDH leakage, distinct from H(2)O(2)-induced apoptosis.
- Cell death was alleviated by necroptosis and autophagy inhibitors (Nec-1, 3-MA), but not apoptosis inhibitors.
- D-gal upregulated necroptosis and autophagy genes (Bmf, Bnip3, Atg5, TIGAR) and activated autophagy, without activating Caspase-3.
- Inhibition of aldose reductase attenuated D-gal toxicity, and D-gal treatment increased AR expression, confirming the polyol pathway's involvement.
Conclusions:
- D-galactose induces non-apoptotic, necroptotic cell death in neuroblastoma cells.
- The aldose reductase-mediated polyol pathway is implicated in D-gal toxicity.
- This finding provides a potential therapeutic strategy for apoptosis-resistant cancers.
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