ULK2 promotes migration and invasion of colorectal cancer cells via MCT4-mediated lactate export.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide. Despite significant advancements in CRC treatment, metastasis remains the primary determinant of CRC-related mortality. Mammalian unc-51 like autophagy activating kinase 1 and 2 (ULK1 and ULK2), which are serine/threonine protein kinases, serve as crucial regulators of autophagy initiation. While the role of ULK1 in tumor biology has been extensively studied, the functional significance of ULK2 in CRC progression remains unexplored. This study investigated ULK2 expression in CRC patient tissues by immunohistochemistry (IHC) and explored its functional and regulatory roles in transfected DLD-1 and SW480 CRC cell lines. ULK2 expression was elevated at the invasive front of CRC, and this elevation showed a positive association with tumor invasion. ULK2 overexpression was associated with EMT-like phenotypic alterations, including loss of membranous E-cadherin and β-catenin nuclear accumulation, which collectively promoted CRC invasion. Furthermore, ULK2 was found to upregulate MCT4 expression on the plasma membrane, resulting in increased extracellular lactate levels and enhanced invasive capacity in vitro. These findings identify ULK2 as a contributing factor to CRC invasion and highlight its therapeutic potential for suppressing tumor aggressiveness.