Antrodia salmonea (AS) is a genus of Antrodia, an epiphyte of Cunninghamia konishii in Taiwan. AS has been reported to have potential therapeutic effects on different diseases, including diarrhea, abdominal pain, and hypertension. AS has been reported to have anticancer effects on numerous cancer types, such as ovarian carcinoma and triple-negative breast cancer. Our previous studies demonstrated that antrocins and triterpenoids are possibly bioactive compositions. However, the effects of AS on prostate cancer remain unknown. Therefore, we investigated the role of AS in prostate cancer growth, apoptosis, and cell cycle regulation. The results showed that AS extracts significantly inhibited the proliferation of prostate cancer LNCaP cells in a dose-dependent manner and increased the levels of apoptotic markers (cleaved PARP and cleaved caspase 3/8/9). In addition, the cell cycle-related proteins CDK1, CDK2, CDK4, and their respective specific regulators Cyclin B1, Cyclin A, and Cyclin D were also affected. Besides, AS treatment increased p53 protein levels and slowed its degradation in LNCaP cells. Interestingly, we found that AS treatment reduced both total protein and Ser-81 phosphorylation levels of the androgen receptor (AR). Notably, the increase of nuclear p53 was accompanied by the down-regulation of AR, suggesting a reverse regulation between p53 and AR in LNCaP cells was triggered by AS treatment. These findings suggest that AS extracts trigger the apoptosis of prostate cancer cells through the reverse regulation of p53 and AR and elucidate that AS extracts might be a potential treatment for androgen-dependent prostate cancer in the near future.
Chemotherapy, in combination with immune checkpoint blockade (ICB) targeting to programmed death‐1 (PD‐1) or its ligand PD‐L1, is one of the first‐line treatments for patients with advanced non–small‐cell lung cancer (NSCLC). However, a large proportion of patients, especially those with PD‐L1 negative tumors, do not benefit from this treatment. This may be due to the existence of multiple immunosuppressive mechanisms other than the PD‐1/PD‐L1 axis. Human leukocyte antigen‐G (HLA‐G) has been identified as an immune checkpoint protein (ICP) and a neoexpressed tumor‐associated antigen (TAA) in a large proportion of solid tumors. In this study, we evaluated the induction of HLA‐G as well as PD‐L1 using sublethal doses of chemotherapeutics including pemetrexed in different NSCLC cell lines. Except for gefitinib, most of the chemotherapeutic agents enhanced HLA‐G and PD‐L1 expression in a dose‐dependent manner, whereas pemetrexed and carboplatin treatments showed the most consistent upregulation of PD‐L1 and HLA‐G in each cell line. In addition to protein levels, a novel finding of this study is that pemetrexed enhanced the glycosylation of HLA‐G and PD‐L1. Pemetrexed potentiated the cytotoxicity of cytotoxic T lymphocytes (CTLs) to treat NSCLC. Both in vitro and in vivo experiments revealed that CTL‐mediated cytotoxicity was most pronounced when both anti‐PD‐L1 and anti‐HLA‐G ICBs were combined with pemetrexed treatment. In conclusion, anti‐HLA‐G could be an intervention strategy in addition to the anti‐PD‐1/PD‐L1 pathway for NSCLC. Moreover, dual targeting of PD‐L1 and HLA‐G combined with pemetrexed might have a better extent of CTL‐based immunotherapy.
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