Abstract
Lung adenocarcinoma (LUAD), which comprises over 50% of all cases of non-small-cell lung cancer, has a poor prognosis and requires novel therapeutic approaches. The sonic Hedgehog (Shh) pathway, which plays a crucial role in differentiation, proliferation, and survival of cancer cells, is likely to be activated in LUADs, suggesting the Shh pathway as a potential therapeutic target for LUAD treatment. In this study, we reported that vismodegib, an inhibitor of the Shh pathway, only elicited minor antitumor efficacy in A549 and NCI-H1975 LUAD cells as well as in the xenograft tumors, with overexpressed GLI2 and increased autophagic activity. The aberrant autophagy in LUAD cells was further confirmed by the three main stages of autophagic flux, including the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Furthermore, inhibition of autophagy by siRNA against ATG5 or ATG7 rescued the sensitivity of A549 and NCI-H1975 LUAD cells to vismodegib in vitro. Meanwhile, administration of the pharmaceutical inhibitor of autophagy, chloroquine, contributed to the enhanced anti-LUAD efficacy of vismodegib in vivo, probably through overproduction of ROS, acceleration of apoptosis, and suppression of GLI2 in LUAD tissues. In summary, our research revealed that downregulating autophagy facilitated the anti-LUAD efficacy of the Shh pathway suppression, thus highlighting a potential approach for LUAD therapy via simultaneously targeting the Shh signaling and autophagy pathway.
Highlights
Lung adenocarcinoma (LUAD), which accounts for~50% of non-small-cell lung cancer (NSCLC), has become one of the leading causes of cancer-related mortality worldwide[1]
Highly activated GLI1 and GLI2 were observed in LUADs12, indicating that the signaling transduction of the sonic Hedgehog (Shh) pathway was abnormally activated in LUADs, and the Shh inhibitors might be a potential therapeutics for LUAD therapy
The SMO agonist SAG significantly enhanced the transcription of GLI1 (Fig. S1), indicating that the Shh singling pathway was likely to be activated in LUAD cells
Summary
Lung adenocarcinoma (LUAD), which accounts for~50% of non-small-cell lung cancer (NSCLC), has become one of the leading causes of cancer-related mortality worldwide[1]. The developed therapies such as platinum and radiotherapy have greatly benefited the management of lung cancer patients, the prognosis of LUAD patients still remains poor, with the 5-year survival rate at ~15%2. Due to its crucial role in differentiation, proliferation, and survival of cancer cells, the Shh signaling pathway has been becoming one of the most promising targets for cancer therapy. Vismodegib (GDC-0449) is the first Shh inhibitor approved for the clinical treatment of basal cell carcinomas (BCC)[4,5]. It could selectively deprive the activity of the Smoothened (SMO) and result in the apoptosis induction and growth inhibition in BCC cells[6,7]. Our preliminary results showed that vismodegib only had minor effect on the LUAD cells with unknown mechanisms
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