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Int J Mol Sci
2018 Nov 01;1911:. doi: 10.3390/ijms19113429.
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Fungal Immunomodulatory Protein from Nectria haematococca Suppresses Growth of Human Lung Adenocarcinoma by Inhibiting the PI3K/Akt Pathway.
Xie Y
,
Li S
,
Sun L
,
Liu S
,
Wang F
,
Wen B
,
Sun L
,
Fang X
,
Chai Y
,
Cao H
,
Jia N
,
Gu T
,
Lou X
,
Xin F
.
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Lung cancer is a common disease that is associated with poor prognosis. Fungal immunomodulatory protein from Nectria haematococca (FIP-nha) has potential as a lung cancer therapeutic; as such, illuminating its anti-tumor mechanism is expected to facilitate novel treatment options. Here, we showed that FIP-nha affects lung adenocarcinoma growth ex vivo and in vivo. Comparative quantitative proteomics showed that FIP-nha negatively regulates PI3K/Akt signaling and induces cell cycle arrest, autophagy, and apoptosis. We further demonstrated that FIP-nha suppresses Akt phosphorylation, leading to upregulation of p21 and p27 and downregulation of cyclin B1, cyclin D1, CDK2, and CDK4 expression, ultimately resulting in G1/S and G2/M cell cycle arrest. Meanwhile, FIP-nha-induced PI3K/Akt downregulation promotes A549 apoptosis by increasing the expression ratio of Bax/Bcl-2 and c-PARP and autophagy by decreasing the phosphorylation of mTOR. Thus, we comprehensively revealed the anti-tumor mechanism of FIP-nha, which inhibits tumor growth by modulating PI3K/Akt-regulated cell cycle arrest, autophagy, and apoptosis, and provided the basis for further application of fungal immunomodulatory proteins, especially FIP-nha.
Figure 1. Inhibitory effects of FIP-nha on ex vivo and in vivo lung adenocarcinoma growth. (A) Effect of FIP-nha on MRC-5, A549 and H2347 cell growth. The cells were treated with FIP-nha (0, 4, 8, 16, or 20 µg/mL) for 24 h. Cell viability was measured by MTT assays. **** p ≤ 0.0001. (B) Inhibition of solid tumor growth in FIP-nha-treated xenograft mice of A549 cells. Images of solid tumors in negative control (PBS), positive control (doxorubicin, 4 mg/kg body weight) and experimental groups (FIP-nha, 20 and 40 mg/kg body weight) are shown. Each group contained 8 mice. Scale bar = 0.5 cm. (C) Effect of FIP-nha on the volume of solid tumors. * p ≤ 0.05 was considered significant. (D) Effect of FIP-nha on body weight. Quantitative data are shown as mean ± SD for tumor volume or body weight measurements.
Figure 3. FIP-nha negatively regulates the PI3K/Akt signaling pathway and induces autophagy in lung adenocarcinoma cells by downregulating p-mTOR. (A) A549 and H2347 cells were treated with 0, 4, 8, and 16 µg/mL FIP-nha for 24 h. The protein expression levels of p-AKT, AKT, p-mTOR, and LC3B-I/II were examined by western blotting. (B) Ultrastructures of autophagosome in A549 cells treated FIP-nha (8 µg/mL) for 24 h. Arrows indicate autophagosome vesicles contained double membranes and damaged organelles. (C) A549 cells were treated with FIP-nha (8 µg/mL) for 24 h and then bafilomycin A1 (50 nM) for another 4 h. The protein levels of LC3B-I/II were examined by western blotting.
Figure 4. FIP-nha induces G1/S and G2/M cell cycle arrest in lung adenocarcinoma cells. (A) A549 and H2347 cells were treated with 8 µg/mL FIP-nha for 24 h and cell cycle distribution was determined by flow cytometry. Untreated cells were used as control. (B) Western blotting analysis of cyclin B1, cyclin D1, CDK2, CDK4, p21, and p27 protein expression in A549 and H2347 cells after exposure to FIP-nha at 0, 4, 8 and 16 µg/mL for 24 h.
Figure 5. FIP-nha induces apoptosis in A549 and H2347 cells. (A) A549 and H2347 cells were incubated with 8 µg/mL FIP-nha for 24 h. Untreated cells were used as control. After labeling with Annexin V-FITC and propidium iodide (PI), apoptotic cells were detected by flow cytometry. (B) The expressions of apoptosis-related proteins c-PARP, Bax, and Bcl-2 were assessed by western blotting.
Figure 6. (A) The levels of p-Akt, cyclin B1, cyclin D1, c-PARP, Bax, Bcl-2, and LC3B-II in xenograft tumors were determined by western blotting. The experimental group (N1 and N2) was treated with 40 mg/kg FIP-nha, and the control group (C1 and C2) was treated with the same volume of PBS. (B) IHC of cleaved caspase 3 and Ki-67 in xenograft tumors. Each group contained three mouse tumors.
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