KDELR3 is transcriptionally activated by FOXM1 and accelerates lung adenocarcinoma growth and metastasis via inhibiting endoplasmic reticulum stress-induced cell apoptosis.

Abstract

Lung cancer is still considered to be the leading cause of cancer-related death worldwide, and lung adenocarcinoma (LUAD) is the most common kind. KDEL Endoplasmic Reticulum Protein Retention Receptor 3 (KDELR3) is a critical regulator of the endoplasmic reticulum (ER) stress and the followed unfolded protein response (UPR) process, which are critical in tumor development. However, the role of KDELR3 in LUAD tumor progression remains poorly understood. In this work, we demonstrated that KDELR3 is significantly upregulated in LUAD tumor tissues and cell lines. Suppression of KDELR3 promoted the phosphorylation level of UPR-related pathways, PERK, and EIF2α in LUAD cell lines. The downregulation of KDELR3 promoted ER stress-induced cell apoptosis, decreased the protein expression of Bcl-2, and increased the protein expression of Bax in LUAD cells. Moreover, the knockdown of KDELR3 inhibits LUAD cell invasion. In vivo animal experiments confirmed that the inhibition of KDELR3 suppresses LUAD tumor growth and metastasis. Mechanistic studies showed that transcription factor FOXM1 may serve as an upstream factor of KDELR3. The upregulation of FOXM1 increased the transcriptional activity of KDELR3. Further results illustrated that FOXM1 directly binds to the promoter of KDELR3, thus upregulating its expression. Finally, rescue experiments demonstrated that FOXM1 inhibition-induced cell apoptosis and invasion could be reversed by KDELR3 overexpression. Overall, our findings indicated that KDELR3 is transcriptionally upregulated by FOXM1 and accelerates tumor growth and lung metastasis in LUAD by inhibiting ER stress-induced cell apoptosis.