# RIOK3 sustains colorectal cancer cell survival under glucose deprivation via an HSP90α-dependent pathway

## TL;DR

This study shows that RIOK3 helps colorectal cancer cells survive in low-glucose environments by boosting NADPH production through an HSP90α-dependent pathway.

## Contribution

The study identifies a novel RIOK3–HSP90α–IDH1 pathway that sustains cancer cell survival under glucose deprivation.

## Key findings

- RIOK3 expression increases under glucose deprivation and is essential for cancer cell survival.
- RIOK3 interacts with HSP90α to enhance IDH1 expression and NADPH production.
- RIOK3 inhibition loses effect in HSP90α-knockdown cells, confirming pathway dependency.

## 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.