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RIOK3 sustains colorectal cancer cell survival under glucose deprivation via an HSP90α-dependent pathway
Nan Zhang1, Lu Dong1,2, Tingting Ning1
1Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, China.
Abstract:
Glucose oxidation via the pentose phosphate pathway serves as the primary cellular mechanism for generating nicotinamide adenine dinucleotide phosphate (NADPH). The central regions of solid tumors typically experience glucose deficiency, emphasizing the need for sustained NADPH production crucial to tumor cell survival. This study highlights the crucial role of RIOK3 in maintaining NADPH production and colorectal cancer (CRC) cell survival during glucose deficiency. Our findings revealed upregulated RIOK3 expression upon glucose deprivation, with RIOK3 knockout significantly reducing cancer cell survival. Mechanistically, RIOK3 interacts with heat shock protein 90α (HSP90α), a chaperone integral to various cellular processes, thereby facilitating HSP90α binding to isocitrate dehydrogenase 1 (IDH1). This interaction further upregulates IDH1 expression, enhancing NADPH production and preserving redox balance. Furthermore, RIOK3 inhibition had no discernible effect on intracellular NADPH levels and cell death rates in HSP90α-knockdown cells. Collectively, our findings suggest that RIOK3 sustains colon cancer cell survival in low-glucose environments through an HSP90α-dependent pathway. This highlights the significance of the RIOK3-HSP90α-IDH1 cascade, providing insights into potential targeted therapeutic strategies for CRC in metabolic stress conditions.
Insights
RIOK3 maintains colorectal cancer cell survival under glucose deficiency by boosting NADPH production. This protein interacts with HSP90α to upregulate IDH1, preserving redox balance and offering potential therapeutic targets.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Glucose metabolism is vital for cancer cell survival, particularly in nutrient-poor tumor microenvironments.
- Nicotinamide adenine dinucleotide phosphate (NADPH) production is essential for maintaining redox balance and enabling tumor growth.
- Pentose phosphate pathway is the primary source of NADPH, crucial for cancer cells under metabolic stress.
Purpose of the Study:
- To investigate the role of RIOK3 in colorectal cancer (CRC) cell survival during glucose deficiency.
- To elucidate the molecular mechanism by which RIOK3 influences NADPH production and cell viability under low-glucose conditions.
Main Methods:
- Analysis of RIOK3 expression in response to glucose deprivation.
- CRISPR-Cas9 mediated knockout of RIOK3 in colorectal cancer cells.
- Investigation of protein-protein interactions using co-immunoprecipitation assays.
- Assessment of NADPH levels and cell viability under various experimental conditions.
Main Results:
- RIOK3 expression is upregulated in colorectal cancer cells upon glucose deprivation.
- RIOK3 knockout significantly impairs cancer cell survival under low-glucose conditions.
- RIOK3 facilitates the interaction between HSP90α and isocitrate dehydrogenase 1 (IDH1), enhancing IDH1 expression and boosting NADPH production.
- The RIOK3-mediated survival effect is dependent on HSP90α, as RIOK3 inhibition does not affect NADPH levels or cell death in HSP90α-knockdown cells.
Conclusions:
- RIOK3 plays a critical role in sustaining colorectal cancer cell survival under glucose-deficient conditions through an HSP90α-dependent pathway.
- The RIOK3-HSP90α-IDH1 cascade is a key mechanism for maintaining NADPH production and redox balance in cancer cells facing metabolic stress.
- Targeting the RIOK3-HSP90α-IDH1 pathway presents a potential therapeutic strategy for colorectal cancer, especially in the context of metabolic stress.
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