title: Inhibition of cervical cancer cell growth through activation of upstream kinases of AMP-activated protein kinase.
abstract: AMP-activated protein kinase (AMPK) is a critical energy-balancing sensor in the regulation of cellular metabolism in response to external stimuli. Emerging evidence has suggested that AMPK is a potential therapeutic target for human cancers. AICAR, one of the pharmacological AMPK activators, has been widely used to suppress cancer cell growth through activation of LKB1, an upstream kinase of AMPK. However, frequent mutations and deletions of LKB1 found in some cancer cells limit the application of AICAR as an efficient therapeutic drug. Here we show that an alternative pharmacological AMPK activator, A23187, was able to inhibit cervical cancer cell growth through activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta, another upstream kinase of AMPK. Using cervical cancer cell models, we found that HeLa (LKB1-deficient cell) responded less to the anti-proliferative effect exerted by AICAR treatment (p < 0.001) compared with CaSki and C41 (LKB1-expressing cells). Conversely, the anti-proliferative effect was increased significantly in HeLa but not in CaSki and C41 cells under treatment by A23187 (p < 0.001). Moreover, co-treatment of AICAR and A23187 was able to further enhance the inhibitory effect on cell growth of Hela, CaSki and C41 cells. Notably, both AICAR and A23187 exerted the anti-proliferative effect on cervical cancer cells by suppressing AMPK/mTOR signalling activity. These data suggest that A23187 could be an alternative potential therapeutic drug used for anti-proliferation in LKB1-deficient cancer cells.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong, China.
authors.forename: Sandy Yee Man
authors.initials: SY
authors.lastname: Yu
authors.forename: David Wai
authors.initials: DW
authors.lastname: Chan
authors.forename: Vincent Wing Sun
authors.initials: VW
authors.lastname: Liu
authors.forename: Hextan Yuen Sheung
authors.initials: HY
authors.lastname: Ngan
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D000001:Calcimycin / Q000627:therapeutic use; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000627:therapeutic use*; D005260:Female; D006131:Growth Inhibitors / Q000627:therapeutic use*; D006367:HeLa Cells; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012265:Ribonucleotides / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics
chemical_list: D020536:Enzyme Activators; D006131:Growth Inhibitors; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000001:Calcimycin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C517698:CAMKK2 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide