Caveolin-1 promotes radioresistance via IRGM-regulated autophagy in lung cancer

Radiotherapy is the standard therapeutic approach for non-small cell lung cancers (NSCLCs). However, radiotherapy resistance accounts for major treatment failures in NSCLC patients. Recently, targeting autophagy-related signaling has shown potential to improve radiotherapy. Furthermore, some studies have reported that caveolin-1 (Cav1), a primary scaffolding protein of caveolae, is positively associated with NSCLC progression and cell autophagy. However, the function of Cav1-mediated autophagy in NSCLC radioresistance remains largely unknown.

The results of our study showed that Cav1 is involved in the development of IR resistance in NSCLC through IRGM-regulated autophagy and can be considered as a potential therapeutic target for improving the radiosensitivity of NSCLC.

The NSCLC irradiation (IR)-resistant cell lines H358-IRR and A549-IRR were used for in vitro analysis. Real-time quantitative PCR (qPCR), western blot, cell counting kit-8 (CCK-8), colony formation and transmission electron microscopy analyses were performed to explore the relationship between Cav1 and immunity-related GTPase family M protein (IRGM)-regulated autophagy in the radiation resistance of lung cancers.

Cav1 was significantly overexpressed in H358-IRR and A549-IRR cells compared to their parental counterparts. Knockdown of Cav1 significantly decreased the proliferation of IR-resistant NSCLC cells. Combinational treatment of IR and siRNA of Cav1 showed enhanced inhibition of the cell viability and colony formation of IR-resistant NSCLC cells. In addition, Cav1 overexpression could upregulate the autophagic proteins microtubule associated protein 1 light chain 3 II (LC3 II), Beclin-1 and Sequestosome 1 (SQSTM1/p62) in parental NSCLC cells, while Cav1 downregulation by siRNA inhibited the expression of LC3 II, Beclin-1 and p62 and the formation of autophagosomes in IR-resistant NSCLC cells. Furthermore, we observed that IRGM was downregulated after knockdown of Cav1 in IR-resistant NSCLC cells. Thus, Cav1 was observed to promote autophagy and increase IR-resistant cell survival by targeting IRGM. Conclusions: The results of our study showed that Cav1 is involved in the development of IR resistance in NSCLC through IRGM-regulated autophagy and can be considered as a potential therapeutic target for improving the radiosensitivity of NSCLC.