Parathyroid hormone-like adenylate cyclase-stimulating activity from a human carcinoma is associated with bone-resorbing activity.
We found previously that a human renal carcinoma cell line derived from a hypercalcemic patient induces humoral hypercalcemia when grown as allografts in the nude mouse and secretes a protein that activates adenylate cyclase via the PTH receptor. The purpose of this study was to examine the conditioned medium of this cell line for bone-resorbing activity in vitro. Processed conditioned medium produced dose-dependent stimulation of bone resorption in cultured fetal rat limb bone explants. Two PTH antagonists were used to assess the PTH receptor dependence of this bone-resorbing activity. Neither [8Nle,18Nle,34Tyr]bovine (b) PTH-(3-34) amide nor [34Tyr]bPTH-(7-34)amide inhibited bone resorption or limb bone cAMP accumulation induced by either processed conditioned medium or equivalent concentrations of bPTH-(1-34). As an alternate means to assess whether this tumor-derived PTH-like protein had intrinsic bone-resorbing activity, the latter was measured during partial purification of PTH-like adenylate cyclase-stimulating activity (ACSA) from conditioned medium by consecutive gel filtration and reverse phase HPLC. The bone-resorbing activity in conditioned medium could not be resolved from PTH-like ACSA by these two separation techniques, indicating that the activities may be intrinsic to the same protein. These results are consistent with the view that a tumor-derived protein with PTH-like ACSA and bone-resorbing activity may be responsible for hypercalcemia in vivo.
D000230:Adenocarcinoma / Q000503:physiopathology*; D000262:Adenylyl Cyclases / Q000494:pharmacology*; D000818:Animals; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D005333:Fetus; D006801:Humans; D007680:Kidney Neoplasms / Q000503:physiopathology*; D007700:Kinetics; D009363:Neoplasm Proteins / Q000302:isolation & purification* / Q000494:pharmacology; D009924:Organ Culture Techniques; D010281:Parathyroid Hormone / Q000302:isolation & purification* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D009363:Neoplasm Proteins; D010281:Parathyroid Hormone; D000242:Cyclic AMP; D000262:Adenylyl Cyclases