Ferulic acid, a phenolic phytochemical, inhibits UVB-induced matrix metalloproteinases in mouse skin via posttranslational mechanisms Vanisree Staniforth a , Wen-Ching Huang a , Kandan Aravindaram a,b , Ning-Sun Yang a, ⁎ a Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC b National Bureau of Plant Genetic Resources, Pusa Campus, New Delhi-110 012, India Received 10 September 2010; received in revised form 20 January 2011; accepted 27 January 2011 Abstract Matrix metalloproteinases MMP-2 and -9 are known to be overexpressed in ultraviolet B (UVB)-irradiated skin tissues and contribute to the acceleration of photoaging and the development of skin cancer. But the specific molecular mechanisms that can control or interfere with the expression and regulation of these MMP-2 and -9 activities in skin are not clearly understood. The aim of the present study was to analyze the suppressive effects of ferulic acid (FA), an abundant phenolic compound present in various dietary and medicinal plants, on UVB radiation-induced MMP-2 and -9 activities in mouse skin. For attenuation of chronic UVB irradiation damage to skin, inhibition of MMP-2 and -9 protein expression was detected using immunohistochemistry analysis. However, the in situ suppressive effects of FA did not interfere with the transcription or translation of MMP-2 and -9, suggesting that its action could be mediated via the proteasome pathway. Histological analyses showed that FA attenuates the degradation of collagen fibers, abnormal accumulation of elastic fibers and epidermal hyperplasia induced by UVB, demonstrating the functional and physiological relevance of FA effects in UVB-irradiated skin tissues. Together, our findings provide a novel and increased insight into the in vivo action of FA and suggest a possible clinical application in skin pathophysiological conditions associated with overexpression of MMP-2 and -9. © 2012 Elsevier Inc. All rights reserved. Keywords: Cell signaling; Matrix metalloproteinase; Inflammation; Invasion; Proteasome 1. Introduction Matrix metalloproteinases (MMPs) were initially characterized as matrix-degrading proteases, which play an important role in remodeling the extracellular matrix in many physiological and pathological processes [1]. However, an increasing number of studies have revealed a wide variety of nonmatrix substrates for MMPs, such as adhesion molecules, receptors, chemokines, cytokines, growth factors, intercellular junction proteins and structural molecules. Proteolytic modification of these molecules by MMPs can confer diverse cellular and molecular activities under normal and disease conditions [2]. Research in recent years has demonstrated a strong association between the deregulated MMP expression and various pathophysiological conditions such as cancer, arthritis, cardiovascular diseases, neurodegenerative disorders and others [3]. The contribu- tion of MMPs to disease processes is further supported by studies of relevant disease models in MMP-deficient animals [4]. Specific MMPs are, therefore, now being considered important therapeutic targets for a number of diseases. Skin cancer, a very prevalent form of cancer in humans, typically occurs in photoaged skin [5,6]. Chronic exposure to UV radiation is the main environmental factor that causes photoaging and photocarci- nogenesis [7]. Increased expression of MMPs and their activities are observed in photodamaged skin [8]. Several different types of cells in the skin such as fibroblasts, keratinocytes, macrophages, endothelial cells, mast cells and eosinophils are known to produce MMPs [9]. Ultraviolet B (UVB) radiation induces the expression of two important MMPs, MMP-2 (gelatinase A) and MMP-9 (gelatinase B), which have been implicated in skin photoaging and photocarcinogenesis [10,11]. Recent evidence further suggests that premature aging can predis- pose skin to cancer development [6]. Basal cell carcinoma (BCC), the most common form of skin cancer, arises within the basal layer of the epidermis and typically occurs in areas of chronic sun exposure [12]. Overexpression of MMP-2 and -9 is observed in stromal cells surrounding malignant epithelial cells in BCC [11]. Squamous cell carcinoma (SCC) is a malignant tumor of keratinocytes of the spinous layer of the epidermis and frequently arises in UV-exposed skin [13]. The growth and aggressiveness of SCC are correlated with a high expression of MMP-2 and -9 [14]. In addition to nonmalignant melanoma, UV radiation has also been implicated in the progression Available online at www.sciencedirect.com Journal of Nutritional Biochemistry 23 (2012) 443 – 451 Abbreviations: UVB, ultraviolet B radiation; FA, ferulic acid; MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; NF-κB, nuclear factor kappa B; Akt, protein kinase B; mTOR, mammalian target of rapamycin; 4E-BP1, eIF4E-binding protein 1; eIF4E, eukaryotic initiation factor 4E; p70S6K, ribosomal p70 S6 protein kinase; S6, ribosomal protein S6; Raptor, regulatory associated protein of mTOR; EGFR, epidermal growth factor receptor. ⁎ Corresponding author. Tel.: +886 2 2787 2067; fax: +886 22651 1127. E-mail address: nsyang@gate.sinica.edu.tw (N.-S. Yang). 0955-2863/$ - see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jnutbio.2011.01.009