Fungal Immunomodulatory Protein from Nectria haematococca Suppresses Growth of Human Lung Adenocarcinoma by Inhibiting the PI3K/Akt Pathway

Abstract

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.

Immunomodulatory Protein from Nectria haematococca Induces Apoptosis in Lung Cancer Cells via the P53 Pathway

“…In early studies, we confirmed that FIP-nha induced A549 cell apoptosis by negatively regulating PI3K/Akt signaling using comparative quantitative proteomics [20]. Because of the complexities of antitumor effects and crosstalk among anti-tumor pathways, 1 H NMR-based metabolomics was applied to investigate A549 cell metabolic signatures after rFIP-nha treatment with the aim of comprehensively understanding the underlying mechanisms and assessing the diagnostic potential of this protein.…”

“…at 8 μg/mL show obvious anti-tumor activity towards human tumor cells [21,26], but FIP-fve did not show anti-tumor activity until the concentration reached 195 μg/mL [22]. In addition to the above FIPs, five other FIPs with excellent direct anti-tumor effects have been identified by our laboratory using genetic engineering methods [20,27,28,29]. Among them, FIP-nha showed the strongest and broad-spectrum anti-tumor activities, and could induce A549 cell apoptosis by G1/S arrest [20].…”

“…In addition to the above FIPs, five other FIPs with excellent direct anti-tumor effects have been identified by our laboratory using genetic engineering methods [20,27,28,29]. Among them, FIP-nha showed the strongest and broad-spectrum anti-tumor activities, and could induce A549 cell apoptosis by G1/S arrest [20]. In this study, we further confirmed that rFIP-nha was significantly toxic to A549 cells but had no effects on normal HEK293 cells.…”

“…In preliminary studies, we identified a FIP from N. haematococca , FIP-nha, that had a strong anti-tumor effect against the human leukemia HL60, gastric cancer MGC823, and liver cancer HepG2 cell lines by activating cell death via apoptosis, and these apoptotic effects were cell-type specific [19]. By conducting comparative quantitative proteomics data analysis, we found that FIP-nha suppressed the growth of human NSCLC A549 cells by negatively regulating the PI3K/Akt signaling pathway [20]. In this study, combined with previous studies, the anti-tumor capacity and effect of rFIP-nha on A549 cells was further investigated.…”

Current Understanding of the Structure and Function of Fungal Immunomodulatory Proteins

“…Although a precise mechanism is still unknown, there are relevant illustrations of some structural-related bioactive functions. For instance, FIP-gts ( 124 ), FIP-nha ( 125 ), and LZ-8 ( 126 ) can be transported into tumor cells and exert toxicity, and LZ-8 could even enter the nucleus of NB4 cells ( 127 ). The way they distinguish tumor cells and normal cells, the vital structure which enters the cell and behaves toxically, and the mechanism of their anti-tumor activity need further investigation.…”