Valrubicin activates PKCa in keratinocytes: a conceivable mode of action in treating hyper-proliferative skin diseases

• Published in: Journal of drugs in dermatology Vol. 12; no. 10; p. 1156
• Main Authors: Laugesen, Ina Groenkjaer, Hauge, Eva, Andersen, Stine Maria, Stenderup, Karin, de Darkó, Elisabeth, Dam, Tomas Norman, Rosada, Cecilia
• Format: Journal Article
• Language: English
• Published: United States 01-10-2013
• Subjects: Antineoplastic Agents - therapeutic use; Cell Differentiation - drug effects; Cell Line; Cell Proliferation - drug effects; Doxorubicin - analogs & derivatives; Doxorubicin - therapeutic use; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Keratinocytes - drug effects; Keratinocytes - enzymology; Lipid Metabolism - drug effects; MAP Kinase Signaling System - drug effects; Membrane Proteins - metabolism; Myristoylated Alanine-Rich C Kinase Substrate; Phosphorylation; Protein Kinase C-alpha - metabolism; Protein Transport - drug effects; Skin Diseases - drug therapy; Skin Diseases - enzymology; Skin Diseases - pathology
• ISSN: 1545-9616

Valrubicin is a semisynthetic anthracycline developed as an anti-cancer drug able to ameliorate psoriasis and non-melanoma skin cancer (NMSC) by topical application in animal models. Valrubicin decreases cell proliferation, and induces apoptosis; however its mode of action is still unknown. Valrubicin localizes in the cytoplasm and its valerate moiety resembles diacylglycerol, an activator of protein kinase C (PKC) α, which belongs to the PKC family of cytoplasmic serine/threonine protein kinases. PKCα is observed in the suprabasal layers of normal skin and is associated to keratinocyte growth arrest and differentiation processes. In hyper-proliferative skin diseases the presence of PKCα is altered.
The aim of the present study was to investigate valrubicin's mode of action in keratinocytes by studying its possible effect on PKCα activation.
PKCα's characteristic to translocate from the cytoplasm to the cellular membrane when activated was assessed by measuring the amount of PKCα in the soluble and membrane-bound protein fractions isolated from valrubicin stimulated keratinocytes and by visualizing PKCα in stimulated cells over time. Downstream signaling was investigated by measuring the amount of phosphorylated Myristoylated Alanine-rich C-kinase substrate (MARCKS) and extracellular signal-regulated kinases (ERK) 1/2 of valrubicin-stimulated keratinocytes. To investigate whether there was a direct interaction between valrubicin and PKCα, an activity assay employing purified PKCα protein was used.
Valrubicin activates PKCα in vitro as shown by PKCα's translocation and phosphorylation of downstream signaling molecules.
Valrubicin stimulates PKCα activity and downstream signaling which may contribute to its beneficial effect in psoriasis and NMSC.