Repurposing homoharringtonine for thyroid cancer therapy through TIMP1/FAK/PI3K/AKT signaling pathway

ABSTRACT: Homoharringtonine (HHT), an alkaloid isolated from Cephalotaxus, is an effective anti-leukemia agent that also exhibits inhibitory effects in various solid tumors. However, the impacts of HHT treatment on thyroid cancer (TC) remain unclear. This study aimed to explore whether HHT has anti-TC effects and its underlying molecular mechanism. Our findings demonstrated that HHT exhibited strong anti-TC activity, both in vivo and in vitro, that involved inhibiting cell proliferation, invasion, and migration, as well as inducing apoptosis. Proteomics analysis revealed that the expression of the tissue inhibitor of metalloproteinase 1 (TIMP1) was downregulated in TC cells following HHT treatment. Overexpression of TIMP1 had the opposite effects of HHT and reversed its inhibitory effects, while TIMP1 downregulation, mimicking the inhibitory effects of HHT, enhanced the anti-TC effects of HHT. Furthermore, the TIMP1 knockdown and rescue experiment revealed that TIMP1 re-expression attenuated the enhancement of anti-TC effects of HHT induced by TIMP1 knockdown. Mechanistically, HHT exerted the anti-TC effects by downregulating TIMP1 expression and then inactivating the FAK/PI3K/AKT signaling pathway. Taken together, the FDA-approved drug HHT could inhibit TC progression by inhibiting the TIMP1/FAK/PI3K/AKT signaling pathway and be repurposed as a promising agent for TC treatment.

ORGANISM(S): Homo Sapiens

SUBMITTER: Quanyong Luo  

PROVIDER: PXD050295 | iProX | Sun Mar 03 00:00:00 GMT 2024

REPOSITORIES: iProX