BHLHE40-mediated upregulation of CAV1 decreases the radiosensitivity of nasopharyngeal carcinoma.

Abstract

Radical radiotherapy remains the standard treatment for nonmetastatic nasopharyngeal carcinoma (NPC). However, a considerable proportion of patients still experience therapeutic failure due to the emergence of radioresistance. The molecular mechanisms underlying this resistance are not fully elucidated, underscoring the need for new biomarkers and therapeutic targets to increase radiosensitivity and improve treatment outcomes. Gene and protein expression were assessed using real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry. Cell viability, proliferation, and apoptosis were evaluated using the cell counting kit-8 assay, colony formation assay, and flow cytometry, respectively. The binding of basic helix-loop-helix family member e40 (BHLHE40) to the caveolin-1 (CAV1) promoter was examined using chromatin immunoprecipitation and a dual luciferase assay. An in vivo NPC xenograft mouse model was also established. CAV1 reduced the radiosensitivity of NPC by activating the protein kinase B (Akt) signaling pathway. BHLHE40 contributed to NPC progression by transcriptionally upregulating CAV1. In addition, exosomes secreted by radioresistant NPC cells promoted angiogenesis in human umbilical vein endothelial cells in a CAV1-dependent manner. This study demonstrated that BHLHE40 reduces NPC radiosensitivity by activating CAV1 and the Akt pathway, with CAV1-containing exosomes enhancing angiogenesis and further accelerating NPC progression. These findings suggest that targeting CAV1 could be a promising therapeutic strategy in NPC, offering a new approach to overcoming radioresistance and enhancing treatment efficacy.NEW & NOTEWORTHY This study reveals that BHLHE40 reduces NPC radiosensitivity by transcriptionally activating CAV1, which in turn activates the Akt pathway. In addition, CAV1-containing exosomes secreted by radioresistant NPC cells promote angiogenesis, further accelerating tumor progression. These findings provide new insights into the molecular mechanisms of NPC radioresistance and suggest that targeting CAV1 could be a promising therapeutic strategy to enhance radiosensitivity and improve treatment outcomes.