Hepatocellular carcinoma cells loss lenvatinib efficacy in vitro through autophagy and hypoxia response-derived neuropilin-1 degradation

Abstract

Despite pharmacological advances such as lenvatinib approval, therapeutic failure of hepatocellular carcinoma (HCC) remains a big challenge due to the complexity of its underlying molecular mechanisms. Neuropilin-1 (NRP1) is a co-receptor involved in several cellular processes associated to chemoresistance development. Since both the double-edged process of autophagy and hypoxia-derived response play crucial roles in the loss of therapeutic effectiveness, herein we investigated the interplay among NRP1, autophagy and hypoxia in development of lenvatinib resistance in HCC cell lines. We first analyzed NRP1 expression levels in human HCC samples from public databases, found significantly increased NRP1 expression in human HCC samples as well as its correlation with advanced tumor and metastasis stages. Among 3 HCC cell lines (HepG2, Huh-7 and Hep3B), Hep3B and Huh-7 cells showed significantly increased NRP1 expression levels and cell migration ability together with higher susceptibility to lenvatinib. We demonstrated that NRP1 gene silencing significantly enhanced the anticancer effects of lenvatinib on Hep3B and Huh-7 cells. Furthermore, lenvatinib suppressed NRP1 expression through promoting autophagy in Hep3B and Huh-7 cells; co-treatment with bafilomycin A1 attenuated the antitumor effects of lenvatinib, and NRP1 silencing prevented this loss of in vitro effectiveness of lenvatinib even in the presence of bafilomycin A1. In addition, exposure to a hypoxic microenvironment significantly decreased NRP1 expression through autophagy in Hep3B and Huh-7 cells. Under hypoxia, HIF-1α directly modulated NRP1 expression; HIF-1α silencing not only enhanced the anticancer effects of combined lenvatinib and hypoxia, but also prevented the loss of effectiveness caused by bafilomycin A1, highlighting the potential role of HIF-1α-derived hypoxia response in the adaptive cellular response to lenvatinib and promoting resistance acquisition by autophagy modulation. Overall, NRP1 may constitute a potential therapeutic target to prevent lenvatinib failure derived from a hypoxia-associated modulation of autophagy in advanced HCC.

Overexpression of the lncRNA HOTAIRM1 promotes lenvatinib resistance by downregulating miR-34a and activating autophagy in hepatocellular carcinoma

“…In recent years, researchers have verified that the autophagy signaling pathway impacts the efficiency of lenvatinib and the prognosis of patients with HCC [ 19 ]. Some studies have also shown that lncRNAs play an important role in autophagy [ 20 ].…”

Curcumol Enhances the Antitumor Effect of Lenvatinib on Hepatocellular Carcinoma Cells

“…Lenvatinib is a new type of multi-kinase inhibitor for HCC treatment. Lenvatinib sensitivity is reported to be regulated by the level of autophagy of tumor cells, and activation of autophagy may be helpful to increase lenvatinib sensitivity [28,29]. Sorafenib could significantly reduce the level of STAT3 phosphorylation in glioma cells, induce autophagy, and thus inhibit tumor cell proliferation [30].…”

HDAC Inhibition Sensitize Hepatocellular Carcinoma to Lenvatinib via Suppressing AKT Activation

“…Numerous studies have determined various factors associated with Lenvatinib resistance, such as Jin et al found that inhibition of receptor tyrosine kinases by Lenvatinib leads to feedback activation of EGFR-PAK2-ERK5 pathways, which reduced the effectiveness of Lenvatinib in HCC 36 . Besides, other mechanisms involved in cell metabolism 37 , epigenetics 38 - 40 , autophagy 41 , 42 , EMT 43 , noncoding RNAs 44 - 47 , and the tumor microenvironment 48 , have also been suggested to be related to HCC Lenvatinib resistance.…”