Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy

Abstract

Breast cancer, the most common cancer in women, usually exhibits intrinsic insensitivity to drugs, even without drug resistance. MUC1 is a highly glycosylated transmembrane protein, overexpressed in breast cancer, contributing to tumorigenesis and worse prognosis. However, the molecular mechanism between MUC1 and drug sensitivity still remains unclear. Here, natural flavonoid apigenin was used as objective due to the antitumor activity and wide availability. MUC1 knockout (KO) markedly sensitized breast cancer cells to apigenin cytotoxicity in vitro and in vivo. Both genetical and pharmacological inhibition significantly enhanced the chemosensitivity to apigenin and clinical drugs whereas MUC1 overexpression conversely aggravated such drug resistance. Constitutively re-expressing wild type MUC1 in KO cells restored the drug resistance; however, the transmembrane domain deletant could not rescue the phenotype. Notably, further investigation discovered that membrane-dependent drug resistance relied on the extracellular glycosylated modification since removing O-glycosylation via inhibitor, enzyme digestion, or GCNT3 (MUC1 related O-glycosyltransferase) knockout markedly reinvigorated the chemosensitivity in WT cells, but had no effect on KO cells. Conversely, inserting O-glycosylated sites to MUC1-N increased the drug tolerance whereas the O-glycosylated deletant (Ser/Thr to Ala) maintained high susceptibility to drugs. Importantly, the intracellular concentration of apigenin measured by UPLC and fluorescence distribution firmly revealed the increased drug permeation in MUC1 KO and BAG-pretreated cells. Multiple clinical chemotherapeutics with small molecular were tested and obtained the similar conclusion. Our findings uncover a critical role of the extracellular O-glycosylation of MUC1-N in weakening drug sensitivity through acting as a barrier, highlighting a new perspective that targeting MUC1 O-glycosylation has great potential to promote drug sensitivity and efficacy.

MUC1 and MUC16: critical for immune modulation in cancer therapeutics

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Glycosylation Targeting: A Paradigm Shift in Cancer Immunotherapy

“…MUC1 is overexpressed in various solid tumors, particularly BC, and has become the most relevant and important antigen in BC-targeted therapy. Studies have shown that the targeted O-GalNAc modification of MUC1 plays a role in changing the chemotherapy tolerance of BC and improving the efficacy of anti-tumor therapy 20 . Mucin antigen vaccines are being actively used to treat various solid tumors.…”

Glycan Metabolic Fluorine Labeling for In Vivo Visualization of Tumor Cells and In Situ Assessment of Glycosylation Variations

“…The glycosylation of proteins, especially cell surface proteins, plays a significant part in the development of many diseases [1–7] . For example, it has been shown in recent years that the glycosylation‐related processes of surface proteins are significantly altered in cancer cells, [4,8] which is closely related to the growth [9] and metastasis [10] of tumors and their capacity for immunosuppression [11–12] and drug resistance [13–14] . This abnormality provides a handle for selective targeting of cancer cells.…”

“…[1][2][3][4][5][6][7] For example, it has been shown in recent years that the glycosylation-related processes of surface proteins are significantly altered in cancer cells, [4,8] which is closely related to the growth [9] and metastasis [10] of tumors and their capacity for immunosuppression [11][12] and drug resistance. [13][14] This abnormality provides a handle for selective targeting of cancer cells. Moreover, this anomaly also offers an entry point for the development of a noninvasive approach to visualize real-time glycosylation fluctuations of surface proteins in cancer cells, which is critical for deepening our understanding on the role of glycosylation in tumor progression.…”