Participation of type II protein kinase A in the retinoic acid-induced growth inhibition of SH-SY5Y human neuroblastoma cells

• Published in: Journal of cellular physiology 2000-03, Vol.182 (3), p.421-428
• Main Authors: Kim, Se Nyun, Kim, Sang Gyun, Park, Sang Dai, Cho-Chung, Yoon S., Hong, Seung Hwan
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Brain Neoplasms; Cell Differentiation - drug effects; Cell Division - drug effects; Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes - genetics; Isoenzymes - metabolism; Neuroblastoma; RNA, Messenger - metabolism; Tretinoin - pharmacology; Tumor Cells, Cultured - cytology; Tumor Cells, Cultured - enzymology
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/(SICI)1097-4652(200003)182:3<421::AID-JCP13>3.0.CO;2-2

To examine the role of protein kinase A (EC 2.7.1.37) isozymes in the retinoic acid‐induced growth inhibition and neuronal differentiation, we investigated the changes of protein kinase A isozyme patterns in retinoic acid–treated SH‐SY5Y human neuroblastoma cells. Retinoic acid induced growth inhibition and neuronal differentiation of SH‐SY5Y cells in a dose‐ and time‐dependent manner. Neuronal differentiation was evidenced by extensive neurite outgrowth, decrease of N‐Myc oncoprotein, and increase of GAP‐43 mRNA. Type II protein kinase A activity increased by 1.5‐fold in differentiated SH‐SY5Y cells by retinoic acid treatment. The increase of type II protein kinase A was due to the increase of RIIβ and Cα subunits. Since type II protein kinase A and RIIβ have been known to play important role(s) in the growth inhibition and differentiation of cancer cells, we further investigated the role of the increased type II protein kinase A by overexpressing RIIβ in SH‐SY5Y cells. The growth of RIIβ‐overexpressing cells was slower than that of parental cells, being comparable to that of retinoic acid‐treated cells. Retinoic acid treatment further increased the RIIβ level and further inhibited the growth of RIIβ‐overexpressing cells, showing strong correlation between the level of RIIβ and growth inhibition. However, RIIβ‐overexpressing cells did not show any sign of neuronal differentiation and responded to retinoic acid in the same way as parental cells. These data suggest that protein kinase A participates in the retinoic acid–induced growth inhibition through the up‐regulation of RIIβ/type II protein kinase A. J. Cell. Physiol. 182:421–428, 2000. © 2000 Wiley‐Liss, Inc.