Induction of Cbl-dependent epidermal growth factor receptor degradation in Ling Zhi-8 suppressed lung cancer

Abstract

Activating mutation of epidermal growth factor receptor (EGFR) is correlated with malignant lung tumor. In our study, we demonstrated that recombinant LZ-8 (rLZ-8), a medicinal mushroom Ganoderma lucidum protein, induced cell cycle arrest and apoptosis by downregulating the expression of wild-type and mutated EGFR and inhibiting EGFR downstream effectors, AKT and ERK1/2 in lung cancer cells. We showed that rLZ-8 effectively inhibited lung cancer progression and suppressed EGFR expression of lung tumor lesions in mouse model. Functional studies revealed that rLZ-8 reduced the amount of EGFR in cell membranes by altering EGFR localization to enhance the EGF-induced degradation of EGFR. Mechanistically, we demonstrated that rLZ-8 bound to EGFR to induce EGFR autophosphorylation at tyrosine1045 and trigger ubiquitination by inducing the formation of EGFR/Cbl complexes, resulting in the degradation of EGFR; however, Cbl-shRNA abolished rLZ-8-induced EGFR degradation. We provide the first evidence showing that rLZ-8 inhibits growth and induces apoptosis of lung cancer cells by promoting EGFR degradation. The current findings therefore suggest a novel anti-cancer function of rLZ-8 that targeting EGFR overexpression or mutation as well as EGFR-dependent processes in cancer cells.

GMI, an Immunomodulatory Protein from Ganoderma microsporum, Potentiates Cisplatin-Induced Apoptosis via Autophagy in Lung Cancer Cells

“…In our previous study, GMI inhibits EGF signaling pathway‐induced metastasis in lung cancer cells . LZ‐8, an immunomodulatory protein from Ganoderma lucidum, bound to EGFR to induce Cbl complexes‐mediated degradation of EGFR, resulting in the decrease of wild‐type and mutated EGFR expression in lung cancer cells . These publications prompt us to exam the inhibiting‐effect of GMI on β‐catenin in EGFR‐mutated lung cancer cells.…”

“…LZ‐8, a fungal immunomodulatory protein from Ganoderma lucidium , suppresses EGFR‐mutant lung cancer cells via inhibiting the expression of EGFR . LZ‐8 reduces that metastasis of lung cancer through inhibiting FAK activity .…”

Ganoderma: A Cancer Immunotherapy Review

“…Moreover, rLz-8 might be a useful chemotherapeutic agent for the treatment of lung cancer because owing the key role of FAK targets in metastasis (Lin and Hsu, 2016 ). In addition, Lin et al reported a novel anticancer effect of rLz-8 through targeting EGFR mutation or overexpression and EGFR-dependent processes in lung cancer cells (Lin et al, 2017 ).…”

Recombinant Ganoderma lucidum Immunomodulatory Protein Improves the Treatment for Chemotherapy-Induced Neutropenia

“…It also served as a potential adjuvant for the development of DNA vaccines for human cancers owing to its stimulatory activity on dendritic cells ( Chu et al., 2011 ). Furthermore, the recombinant LZ-8 (rLZ-8) induced the degradation of epidermal growth factor receptor (EGFR) in a clathrin-mediated, endocytosis-dependent, and c-Cbl ubiquitination-dependent manner, which in turn, inhibited proliferation and promoted apoptosis of lung cancer cells ( Lin et al., 2017 ). Currently, the class of chemicals or proteins that exhibit the anti-cancer effects, as well as maintain the homeostasis of immune cells are not identified.…”