title: Pleiotropic roles of Ca+2/calmodulin-dependent pathways in regulating cadmium-induced toxicity in human osteoblast-like cell lines.
abstract: The heavy metal cadmium is a widespread environmental contaminant that has gained public attention due to the global increase in cadmium-containing electronic waste. Human exposure to cadmium is linked to the pathogenesis of osteoporosis. We previously reported cadmium induces apoptosis and decreases alkaline phosphatase mRNA expression via extracellular signal-regulated protein kinase (ERK) activation in Saos-2 bone-forming osteoblasts. This study examines the mechanisms of cadmium-induced osteotoxicity by investigating roles of Ca+2/calmodulin-dependent protein kinase (CAMK) pathways. Saos-2 or MG-63 cells were treated for 24 or 48h with 5μM CdCl2alone or in combination with calmodulin-dependent phosphodiesterase (PDE) inhibitor CGS-9343β; calmodulin-dependent kinase kinase (CAMKK) inhibitor STO-609; or calmodulin-dependent kinase II (CAMKII) inhibitor KN-93. CGS-9343β protected against cadmium-induced toxicity and attenuated ERK activation; STO-609 enhanced toxicity and exacerbated ERK activation, whereas KN-93 had no detectable effect on cadmium-induced toxicity. Furthermore, CGS-9343β co-treatment attenuated cadmium-induced apoptosis; but CGS-9343β did not recover cadmium-induced decrease in ALP activity. The major findings suggest the calmodulin-dependent PDE pathway facilitates cadmium-induced ERK activation leading to apoptosis, whereas the CAMKK pathway plays a protective role against cadmium-induced osteotoxicity via ERK signaling. This research distinguishes itself by identifying pleiotropic roles for CAMK pathways in mediating cadmium's toxicity in osteoblasts.
authors: Department of Biology, The College of Idaho, 2112 Cleveland Blvd, Caldwell, ID 83605, USA.
authors: Thao T
authors: TT
authors: Ha
authors: Department of Biology, The College of Idaho, 2112 Cleveland Blvd, Caldwell, ID 83605, USA.
authors: Shalimar T
authors: ST
authors: Burwell
authors: Department of Biology, The College of Idaho, 2112 Cleveland Blvd, Caldwell, ID 83605, USA.
authors: Matthew L
authors: ML
authors: Goodwin
authors: Department of Biology, The College of Idaho, 2112 Cleveland Blvd, Caldwell, ID 83605, USA.
authors: Jacob A
authors: JA
authors: Noeker
authors: Department of Biology, The College of Idaho, 2112 Cleveland Blvd, Caldwell, ID 83605, USA. Electronic address: sheggland@collegeofidaho.edu.
authors: Sara J
authors: SJ
authors: Heggland
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002104:Cadmium / Q000819:agonists / Q000737:chemistry / Q000633:toxicity*; D020013:Calcium Signaling / Q000187:drug effects*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002147:Calmodulin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D004785:Environmental Pollutants / Q000819:agonists / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007928:Lethal Dose 50; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053644:Naphthalimides / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001562:Benzimidazoles; D001596:Benzylamines; D015415:Biomarkers; D002104:Cadmium; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002147:Calmodulin; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004785:Environmental Pollutants; D053644:Naphthalimides; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C000607143:CALM1 protein, human; C458525:STO 609; C052087:CGS 9343B; C072105:KN 93; D000096926:Benzenesulfonamides
keywords: Apoptosis; Cadmium; Calmodulin; Osteoblast