# Sodium butyrate-induced autophagy in colorectal cancer unveils the Ca²⁺/CaMKKβ signaling pathway as a potential therapeutic target

## TL;DR

Sodium butyrate promotes autophagy in colorectal cancer cells through a calcium signaling pathway, suggesting a new therapeutic target.

## Contribution

The study identifies the Ca²⁺/CaMKKβ signaling pathway as a novel mechanism for sodium butyrate-induced autophagy in colorectal cancer.

## Key findings

- Sodium butyrate upregulates autophagy-related proteins like LC3 in colorectal cancer cells.
- Inhibiting CaMKKβ reduces the autophagic effect of sodium butyrate.
- Cytoplasmic calcium sequestration diminishes sodium butyrate-induced autophagy.

## Abstract

Colorectal cancer’s autophagy process is facilitated by sodium butyrate (NaB), but the mechanism remains unclear. This study aimed to elucidate the effects and underlying mechanisms of NaB-induced autophagy in colorectal cancer cells. In colorectal cancer cells, NaB has been shown to upregulate the expression of autophagy-related proteins, including microtubule-associated protein 1 A/1B-light chain 3 (LC3), thereby promoting autophagosome formation. Furthermore, NaB induces the activation of Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ), AMP-activated protein kinase α (AMPKα), and acetyl-CoA carboxylase (ACC). Moreover, inhibiting CaMKKβ with STO-609 or downregulating CaMKKβ expression using RNA interference significantly attenuated the autophagic effect induced by NaB in colorectal cancer cells, leading to reduced expression of phosphorylated CaMKKβ, AMPKα, and ACC proteins. Furthermore, sequestering cytoplasmic calcium has been found to diminish NaB-induced autophagy and partially inhibit the activation of CaMKKβ, AMPKα, and ACC proteins. The findings indicate that NaB stimulates autophagy in colorectal cancer cells by modulating Ca2+/CaMKKβ signaling pathways.

The online version contains supplementary material available at 10.1038/s41598-025-29618-7.