Effects of bortezomib in sensitizing human prostate cancer cell lines to NK-mediated cytotoxicity
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Wei Hu1, Rui-Rui Zheng, Hui-Xia Cui
1Cancer Research Institute, First Affiliated Hospital, China Medical University, Shenyang 110001, China.
Abstract:
The proteasome inhibitor, bortezomib, has been demonstrated to sensitize tumor cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Natural killer (NK) cells represent potent antitumor effector cells. They also express TRAIL. Therefore, we investigated whether bortezomib could sensitize tumor cells to NK cell-mediated killing, and have the same effect in human prostate cancer cell lines (LNCaP and DU145). We found that bortezomib strongly inhibits proliferation in both cell lines. Furthermore, compared with LNCaP cells, DU145 cells are more sensitive to bortezomib-induced apoptosis. However, bortezomib is unable to sensitize these two cell lines to NK cell-mediated killing in short-term assays. In long-term assays, we found that killing mediated by activated NK cells following bortezomib treatment leads to greater antitumor effects than either treatment alone. In addition, treatment with bortezomib causes these cells to upregulate apoptosis-related mRNA as well as death receptors and downregulate the major histocompatibility class (MHC)-I molecule on the cell surface of DU145 cells. In contrast, LNCaP cells are not sensitized by this treatment. Death receptors and the MHC-I molecule did not change in this cell line. These data suggest that bortezomib can be used to sensitize prostate cancer cells to NK cell-mediated killing and improve current cancer therapies. This therapeutic strategy may be more effective in patients with androgen-insensitive prostate cancer.
Insights
Bortezomib enhances natural killer (NK) cell killing of prostate cancer cells, particularly androgen-insensitive types. This combination therapy shows greater antitumor effects than single treatments alone.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Proteasome inhibitor bortezomib sensitizes tumor cells to TRAIL-mediated apoptosis.
- Natural killer (NK) cells are potent antitumor effector cells expressing TRAIL.
Purpose of the Study:
- Investigate bortezomib's ability to sensitize human prostate cancer cell lines (LNCaP and DU145) to NK cell-mediated killing.
- Evaluate the combined therapeutic effects of bortezomib and NK cells.
Main Methods:
- Treatment of LNCaP and DU145 cells with bortezomib.
- Short-term and long-term assays using activated NK cells.
- Analysis of apoptosis-related mRNA, death receptors, and MHC-I molecule expression.
Main Results:
- Bortezomib inhibits proliferation in both cell lines; DU145 cells are more sensitive to bortezomib-induced apoptosis.
- Bortezomib did not sensitize cells to NK cell killing in short-term assays.
- Long-term assays showed enhanced antitumor effects with combined bortezomib and NK cell treatment.
- Bortezomib upregulated apoptosis-related mRNA and death receptors while downregulating MHC-I in DU145 cells, but not LNCaP cells.
Conclusions:
- Bortezomib can sensitize prostate cancer cells to NK cell-mediated killing, improving therapeutic outcomes.
- This strategy may be particularly effective for androgen-insensitive prostate cancer.
- Differential responses between LNCaP and DU145 cells highlight the complexity of bortezomib's effects on cancer cells.
