Cordycepin and a preparation from Cordyceps militaris inhibit malignant transformation and proliferation by decreasing EGFR and IL-17RA signaling in a murine oral cancer model

Abstract

Cordyceps militaris (CM) and its active ingredient cordycepin have been reported to inhibit tumor growth, but the mechanisms are not fully understood. This study used a mouse model for oral cancer and a cell line, 4NAOC-1 derived from the model to study the mechanisms. Our results show that a CM preparation (CMP) can significantly inhibit tumor development and malignant transformation in the model. In vitro data indicate that CMP and cordycepin can inhibit 4NAOC-1 cell proliferation, either anchorage-dependent or -independent. Cordycepin can also increase cell apoptosis, and decrease cell mitosis and EGFR signaling. In accordance, CMP treatment can significantly decrease the levels of ki-67 and EGFR signaling molecules in cancer tissues. We also found that the levels of IL-17A in cancer tissues of control mice were significantly increased, and CMP inhibited these levels. IL-17A can stimulate cancer cell proliferation, which can be suppressed by cordycepin. Furthermore, cordycepin can reduce the expression of IL-17RA and its downstream signaling molecules. Moreover, CMP and cordycepin can significantly decrease IL-17A production in vitro and in vivo. Finally, CMP and its ingredients can enhance tumoricidal activities with increase in IFN-γ and TNFα, and decrease PD-L1 expression. In conclusion, CMP and its ingredient cordycepin can inhibit tumor growth and malignant transformation in a mouse model for oral cancer via inhibition of EGFR- and IL-17RA-signaling and enhancement of anti-tumor immunity.

5‐hydroxytryptophan attenuates imiquimod‐induced psoriasiform dermatitis probably through inhibition of IL‐17A production and keratinocyte activation

“…The IL‐17A/IL‐17RA signalling in epidermal cells involved Erk1/2 and STAT3 activation and resulted in cytokine (IL‐6 and IL‐8) production . IL‐17A induced STAT3 activation in keratinocytes, which resulted in keratin 17 hyper‐expression .…”

The potential application of Cordyceps in metabolic‐related disorders

“…3′‐dATP induced DNA double‐strand breaks, blocked the synthesis of heterogeneous nuclear RNA (hnRNA) and ribosomal RNA (rRNA) precursors via the inhibition on RNA polymerase I and II, impeded the maturation of pre‐messenger RNA (mRNA) and subsequent protein synthesis by competitively inhibiting the poly(A) polymerase‐mediated polyadenylation of pre‐mRNA, and induced cell apoptosis and cell cycle arrest, which together were involved in the antibacterial, antifungal, antiviral, and antitumor activities (Baik et al, ; Lee et al, ; Lee et al, ; Rose, Bell, & Jacob, ). In addition, 3′‐dATP interfered with the binding of ATP, prevented EGFR phosphorylation and its downstream signaling, and inhibited tumor cell proliferation and malignant transformation (Hsu et al, ; Wang et al, ). Cordycepin and/or 3′‐dATP could also promote tumoricidal activities via the enhanced secretion of interferon‐γ and TNF‐α from splenocytes and the downregulation of PD‐L1 expression in tumor cells (Hsu et al, ).…”

“…In addition, 3′‐dATP interfered with the binding of ATP, prevented EGFR phosphorylation and its downstream signaling, and inhibited tumor cell proliferation and malignant transformation (Hsu et al, ; Wang et al, ). Cordycepin and/or 3′‐dATP could also promote tumoricidal activities via the enhanced secretion of interferon‐γ and TNF‐α from splenocytes and the downregulation of PD‐L1 expression in tumor cells (Hsu et al, ). Notably, cordycepin demonstrated potent antiviral and antitumor activity while showing marginal cytotoxicity against host cells (de Julian‐Ortiz et al, ; Kodama et al, ).…”

Molecular networking as a dereplication strategy for monitoring metabolites of natural product treated cancer cells

“…In the study reported here, we aimed for the structural elucidation of specialized metabolites derived from C. militaris , and specifically the metabolic impact in leukemia cells. Previous studies showed that the crude extract of C. militaris has abundant cordycepin, especially in the form of fruiting body in the mushroom‐based fungus . To gain more chemical insights into the interaction between the specialized metabolome of Cordyceps and human cancer cells, we collected the crude extract of fruiting body of C. militaris for liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis.…”

“…Previous studies showed that the crude extract of C. militaris has abundant cordycepin, especially in the form of fruiting body in the mushroom-based fungus. 37,38 To gain more chemical insights into the interaction between the specialized metabolome of Cordyceps and human cancer cells, we collected the crude extract of fruiting body of C. militaris for liquid chromatography/ water bath for 30 min of sonication and left to stand for 2 h. The sample mixtures were centrifuged at 4000 rpm (Eppendorf 5810R) at room temperature for 20 min. 39 The supernatant was collected and then filtered to remove undissolved substances.…”