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 CAV1 is acting like an oncogene or tumor suppressor gene. We found that CAV1 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. CAV1 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 CAV1 promoter methylation (P < 0.0001) such that CAV1 methylation was found in 93% of SCLCs (n = 15) and 9% of NSCLCs (n = 11), whereas 5-aza-2'deoxycytidine treatment restored CAV1 expression in SCLCs. Exogenous CAV1 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 CAV1 led to inhibition of cellular proliferation and soft-agar and liquid colony formation. Importantly, CAV1 knockdown led to reduced phospho-focal adhesion kinase and RalA, but not RalB, levels in NSCLC cells. These results suggest different roles for CAV1 in SCLC, where CAV1 acts like a tumor suppressor gene, and NSCLC, where it appears required for survival and growth.
Sunaga
Noriaki
N
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center at Dallas, 75390, USA.
Miyajima
Kuniharu
K
Suzuki
Makoto
M
Sato
Mitsuo
M
White
Michael A
MA
Ramirez
Ruben D
RD
Shay
Jerry W
JW
Gazdar
Adi F
AF
Minna
John D
JD
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D003062:Codon; D019175:DNA Methylation; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D020725:ral GTP-Binding Proteins
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D003062:Codon; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020558:GTP Phosphohydrolases; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins