Inhibitory role of proguanil on the growth of bladder cancer via enhancing EGFR degradation and inhibiting its downstream signaling pathway to induce autophagy

Abstract

A major reason for the high mortality of patients with bladder cancer (BC) is that chemotherapy and surgery are only effective for very limited patients. Thus, developing novel treatment options becomes an urgent need for improving clinical outcomes and the quality of life for BC patients. Here, we demonstrated that proguanil significantly inhibited the growth of BC in vitro and in vivo. Importantly, our results indicated that the sensitivity of BC cells to proguanil is positively correlated with the expression of epidermal growth factor receptor (EGFR). Mechanistically, proguanil specifically targeted EGFR and promoted EGFR binding to Caveolin-1, enhanced its endocytosis in a Clathrin-independent manner, and then recruited c-Cbl to promote EGFR ubiquitination and degradation through the lysosomal pathway. Further studies suggested that proguanil induced autophagy by destabilizing EGFR and inhibiting its downstream signaling pathway. Thus, this study reveals the novel mechanism of proguanil on anticancer activity and implies the potential benefits of this drug in the treatment of BC.

Epidermal growth factor regulates autophagy activity and endocytosis of yak cumulus cells in a concentration-dependent manner

“…Under the action of EGF, EGFR rapidly leaves the endoplasmic capsule/lipid raft and undergoes signal transduction and endocytosis ( 37 ). When EGFR internalizes redundancy, cells can degrade it through the lysosome pathway, making EGFR return to the membrane ( 38 ). Therefore, it is speculated that the LC3I protein expression is increased and autophagosomes are generated to degrade excessive internalized EGFR and maintain cell homeostasis when the EGF concentration is higher than 150 ng/mL.…”

Synergistic augmentation of osimertinib‐induced autophagic death by proguanil or rapamycin in bladder cancer

“…PD‐1/PD‐L1 inhibitors and FGFR3 inhibitors have been approved for the clinical treatment of unresectable or metastatic BC, but their side effects and drug resistance of them have largely limited their effect. 2 Thus, exploring new targeted therapies for BC has been an urgent clinic demand. Previous research has determined that EGFR is highly expressed in BC, 2 indicating that EGFR may be an effective target for the treatment of BC.…”

“… 2 Thus, exploring new targeted therapies for BC has been an urgent clinic demand. Previous research has determined that EGFR is highly expressed in BC, 2 indicating that EGFR may be an effective target for the treatment of BC. However, the use of first‐generation EGFR TKIs including erlotinib and monoclonal antibodies including cetuximab to treat BC patients in clinical trials have not shown the desired therapeutic effect.…”

“…However, the use of first‐generation EGFR TKIs including erlotinib and monoclonal antibodies including cetuximab to treat BC patients in clinical trials have not shown the desired therapeutic effect. 2 , 3 Therefore, it is necessary to explore more effective targeted drugs to treat BC patients.…”

“…Studies have shown that there are four main ways of cell death, which are named apoptosis, ferroptosis, autophagic cell death (ACD), and necrosis. 4 As EGFR and its downstream signaling pathways are closely related to autophagy regulation in various cancers, and targeting EGFR‐mediated autophagy is a potential strategy for cancer treatment, 2 we explored whether osimertinib could induce autophagy by inhibiting EGFR and its downstream signaling pathways in BC. Because the conversion of LC3 from LC3‐I to LC3‐II is a specific indicator of the autophagy process, we first detected the changes of LC3‐I/II and found that LC3B‐II/LC3‐I increased.…”