Implication of AMP-activated protein kinase and Akt-regulated survivin in lung cancer chemopreventive activities of deguelin.
Survivin plays important roles in maintaining cell proliferation and survival and promoting tumorigenesis. The present study was conducted to determine the stage of lung carcinogenesis at which survivin expression is induced and to investigate how survivin affects the chemopreventive action of deguelin. In in vitro studies, we observed higher levels of survivin expression in a subset of premalignant and malignant human bronchial epithelial (HBE) and non-small-cell lung cancer (NSCLC) cell lines than in normal HBE cells, and in in vivo studies, a higher level of survivin expression in specimen of human lung dysplasia than in normal lung specimens. Treatment with deguelin inhibited de novo synthesis of survivin protein and induced apoptosis, resulting in suppression of transformation phenotypes, in the premalignant and malignant HBE and NSCLC cell lines. Deguelin inhibited survivin expression in tuberous sclerosis complex 2 (TSC2) wild-type mouse embryonic fibroblasts (MEF) but not in TSC2-knockout MEFs in which mammalian target of rapamycin (mTOR) is constitutively active. Deguelin induced activation of AMP-activated protein kinase (AMPK) and inactivation of Akt. Overexpression of constitutively active Akt abolished deguelin-induced modulation of AMPK activity and survivin expression. Conversely, inactivation of AMPK by compound C or AMPKalpha1/2 small interfering RNA restored Akt and mTOR activities and survivin expression in deguelin-treated HBE cells. These results suggest that survivin expression is induced as an early event in lung carcinogenesis, and deguelin acts as a chemopreventive agent by inducing a reciprocal regulation between AMPK and Akt, resulting in the inhibition of mTOR-mediated survivin.
Jin
Quanri
Q
Department of Thoracic/Head and Neck Medical Oncology,The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Feng
Lei
L
Behrens
Carmen
C
Bekele
B Nebiyou
BN
Wistuba
Ignacio I
II
Hong
Waun-Ki
WK
Lee
Ho-Young
HY
D055372:AMP-Activated Protein Kinases; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D002453:Cell Cycle; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000201:enzymology / Q000503:physiopathology* / Q000517:prevention & control; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077022:Survivin; D014162:Transfection; D014475:Uncoupling Agents / Q000494:pharmacology
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D014475:Uncoupling Agents; D012402:Rotenone; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C107676:deguelin