Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer

Caveolin-1 (CAV1), an essential structural constituent of caveolae that plays an important role in cellular processes such as transport and signaling, has been implicated in the development of human cancers. However, it is unclear whether CAVI is acting like an oncogene or tumor suppressor gene. We found that CAVI expression was reduced or absent in 95% of small cell lung cancers (SCLCs; n = 21 lines), whereas it was retained in 76% of non-small cell lung cancers (NSCLCs; n = 25 lines) compared with normal human lung epithelial cultures, where it was abundantly expressed. CAVI expression was tightly linked to the ability to grow attached to the plastic cell culture surface, whereas CAV1-nonexpressing lung cancers of both SCLC and NSCLC type grew as suspension cultures. In addition, attached lung cancer cultures expressed phosphorylated focal adhesion kinase, whereas suspension cultures did not. Lack of CAV1 expression was tightly associated with CAVI promoter methylation (P < 0.0001) such that CAVI methylation was found in 93% of SCLCs (n = 15) and 9% of NSCLCs (n = 11), whereas 5-aza-2'-deoxycytidine treatment restored CAVI expression in SCLCs. Exogenous CAVI expression in SCLCs significantly inhibited soft-agar colony formation but did not lead to attachment. By contrast, CAV1 knockdown in NSCLCs mediated by small interfering RNA against CAVI led to inhibition of cellular proliferation and soft-agar and liquid colony formation. Importantly, CAVI knockdown led to reduced phospho-focal adhesion kinase and RaIA, but not RalB, levels in NSCLC cells. These results suggest different roles for CAVI in SCLC, where CAVI acts like a tumor suppressor gene, and NSCLC, where it appears required for survival and growth.