title: Lovastatin induces multiple stress pathways including LKB1/AMPK activation that regulate its cytotoxic effects in squamous cell carcinoma cells.
abstract: BACKGROUND
  Cellular stress responses trigger signaling cascades that inhibit proliferation and protein translation to help alleviate the stress or if the stress cannot be overcome induce apoptosis. In recent studies, we demonstrated the ability of lovastatin, an inhibitor of mevalonate synthesis, to induce the Integrated Stress Response as well as inhibiting epidermal growth factor receptor (EGFR) activation.
  
  
  RESULTS
  In this study, we evaluated the effects of lovastatin on the activity of the LKB1/AMPK pathway that is activated upon cellular energy shortage and can interact with the above pathways. In the squamous cell carcinoma (SCC) cell lines SCC9 and SCC25, lovastatin treatment (1-25 µM, 24 hrs) induced LKB1 and AMPK activation similar to metformin (1-10 mM, 24 hrs), a known inducer of this pathway. Lovastatin treatment impaired mitochondrial function and also decreased cellular ADP/ATP ratios, common triggers of LKB1/AMPK activation. The cytotoxic effects of lovastatin were attenuated in LKB1 null MEFs indicating a role for this pathway in regulating lovastatin-induced cytotoxicity. Of clinical relevance, lovastatin induces synergistic cytotoxicity in combination with the EGFR inhibitor gefitinib. In LKB1 deficient (A549, HeLa) and expressing (SCC9, SCC25) cell lines, metformin enhanced gefitinib cytotoxicity only in LKB1 expressing cell lines while both groups showed synergistic cytotoxic effects with lovastatin treatments. Furthermore, the combination of lovastatin with gefitinib induced a potent apoptotic response without significant induction of autophagy that is often induced during metabolic stress inhibiting cell death.
  
  
  CONCLUSIONS
  Thus, targeting multiple metabolic stress pathways including the LKB1/AMPK pathway enhances lovastatin's ability to synergize with gefitinib in SCC cells.
authors.affiliation: Centre for Cancer Therapeutics, The Ottawa Hospital Research Institute, Ontario, Canada.
authors.forename: Laurie
authors.initials: L
authors.lastname: Ma
authors.forename: Nima
authors.initials: N
authors.lastname: Niknejad
authors.forename: Ivan
authors.initials: I
authors.lastname: Gorn-Hondermann
authors.forename: Khalil
authors.initials: K
authors.lastname: Dayekh
authors.forename: Jim
authors.initials: J
authors.lastname: Dimitroulakos
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000077156:Gefitinib; D017353:Gene Deletion; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D011799:Quinazolines; D008687:Metformin; D008148:Lovastatin; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000077156:Gefitinib