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Core2 O-glycan-expressing prostate cancer cells are resistant to NK cell immunity
Teppei Okamoto1, Mihoko Sutoh Yoneyama, Shingo Hatakeyama
1Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
Abstract:
Core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) forms an N-acetylglucosamine branch in the O-glycans (core2 O-glycans) of cell surface glycoproteins. We previously revealed that the expression of C2GnT is positively correlated with poor prognosis in prostate cancer patients. However, the detailed mechanisms underlying their poor prognosis remain unclear. In the current study, we report that the core2 O-glycans carried by the surface MUC1 glycoproteins of prostate cancer cells play an important role in the evasion of NK cell immunity. In C2GnT‑expressing prostate cancer cells, the MUC1 core2 O-glycans are modified with poly-N-acetyllactosamine. MUC1 glycoproteins carrying poly-N-acetyllactosamine attenuated the interaction of the cancer cells with NK cells, resulting in decreased secretion of granzyme B by the NK cells. Poly‑N‑acetyllactosamine also interfered with the ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to access the cancer cell surface. These effects of poly-N-acetyllactosamine on NK cells render C2GnT-expressing prostate cancer cells resistant to NK cell cytotoxicity. By contrast, C2GnT-deficient prostate cancer cells carrying a lower amount of poly-N-acetyllactosamine than the C2GnT-expressing prostate cancer cells were significantly more susceptible to NK cell cytotoxicity. Our results strongly suggest that C2GnT-expressing prostate cancer cells evade NK cell immunity and survive longer in the host blood circulation, thereby resulting in the promotion of prostate cancer metastasis.
Insights
Core2 O-glycans on MUC1 glycoproteins, regulated by Core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT), enable prostate cancer cells to evade NK cell immunity. This promotes cancer cell survival and metastasis.
Area of Science:
- Glycobiology
- Cancer Immunology
- Prostate Cancer Research
Background:
- Core2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) modifies O-glycans on cell surface glycoproteins.
- C2GnT expression correlates with poor prognosis in prostate cancer.
- Mechanisms of C2GnT-mediated poor prognosis in prostate cancer are not fully understood.
Purpose of the Study:
- To investigate the role of core2 O-glycans on MUC1 glycoproteins in prostate cancer cell evasion of NK cell immunity.
- To elucidate the mechanisms by which C2GnT expression influences prostate cancer progression and metastasis.
Main Methods:
- Analysis of MUC1 glycoproteins and core2 O-glycans in C2GnT-expressing and C2GnT-deficient prostate cancer cells.
- Assessment of NK cell interactions, granzyme B secretion, and TRAIL-mediated apoptosis.
- Evaluation of NK cell cytotoxicity against prostate cancer cells with varying C2GnT expression levels.
Main Results:
- MUC1 glycoproteins on C2GnT-expressing prostate cancer cells are modified with poly-N-acetyllactosamine.
- Poly-N-acetyllactosamine on MUC1 attenuates NK cell interaction, reduces granzyme B secretion, and hinders TRAIL-induced apoptosis.
- C2GnT-expressing prostate cancer cells exhibit resistance to NK cell cytotoxicity, while C2GnT-deficient cells are more susceptible.
Conclusions:
- C2GnT-expressing prostate cancer cells evade NK cell immunity through MUC1 core2 O-glycan modification with poly-N-acetyllactosamine.
- This evasion mechanism promotes cancer cell survival in circulation and facilitates prostate cancer metastasis.
- Targeting C2GnT or its glycan products may offer therapeutic strategies for prostate cancer.
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