Beta-site Amyloid Precursor Protein Cleaving Enzyme 1 Overexpression Abrogates ST6GAL1 Mediated Rectal Cancer Chemoradiation Resistance

BACKGROUND/AIM: Sialyltransferase ST6GAL1 is known to be upregulated in various cancer types, including rectal cancer, and is linked to poor prognosis. This enzyme catalyzes the addition of sialic acids to various proteins, altering their activity and function. Our lab has previously shown that ST6GAL1 causes resistance to chemoradiation therapy (CRT) in rectal cancer, via sialylation of tumor necrosis factor receptor 1 (TNFR1). This leads to decreased TNFR1 mediated cell death/apoptosis. We aimed to elucidate whether beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which cleaves ST6GAL1, has a role in treatment response to CRT and whether its overexpression (OE) could improve response to CRT. MATERIALS AND METHODS: We first assessed BACE1 and ST6GAL1 in pre-treatment biopsies from rectal cancer patients. We then evaluated the effects of BACE1 modulation in CRC cell lines. The high BACE1-expressing CRC cell line SW1463 was utilized for inhibition studies, and SW620 CRC cells lines were additionally lentivirally transfected for OE of BACE1 (validated by flow cytometry, qPCR, Western Blotting, and activity assay). BACE1 OE cells were also utilized for response to CRT. RESULTS: Analysis of patient biopsies showed that BACE1 mRNA was significantly increased in patients with a complete response to CRT. SW1463 colorectal cancer cells treated with a BACE1 inhibitor had increased cell-surface sialylation and increased survival after CRT compared to vehicle-treated cells. BACE1 overexpressing SW620 CRC clones exhibited protein expression and activity of BACE1, with reduced ST6GAL1 protein. BACE1 OE colorectal cancer cells also had significantly increased apoptosis and decreased survival after CRT. BACE1 OE clones had decreased sialylation of the apoptosis receptor, TNFR1. CONCLUSION: Collectively, we found that overexpressing BACE1 altered ST6GAL1-mediated CRT resistance in CRC cells. BACE1 enzymatic cleavage of ST6GAL1 may be a potential target for improving therapeutic response to CRT in rectal cancer.