Abstract
The major cause of ovarian cancer treatment failure in cancer patients is inherent or acquired during treatment drug resistance of cancer. Matrix Gla protein (MGP) is a secreted, non-collagenous extracellular matrix protein involved in inhibition of tissue calcification. Recently, MGP expression was related to cellular differentiation and tumor progression. A detailed MGP expression analysis in sensitive (A2780) and resistant to paclitaxel (PAC) (A2780PR) and topotecan (TOP) (A2780TR) ovarian cancer cell lines and their corresponding media was performed. MGP mRNA level (real time PCR analysis) and protein expression in cell lysates and cell culture medium (Western blot analysis) and protein expression in cancer cells (immunofluorescence analysis) and cancer patient lesions (immunohistochemistry) were determined in this study. We observed increased expression of MGP in PAC and TOP resistant cell lines at both mRNA and protein level. MGP protein was also detected in the corresponding culture media. Finally, we detected expression of MGP protein in ovarian cancer lesions from different histological type of cancer. MGP is an important factor that might contribute to cancer resistance mechanism by augmenting the interaction of cells with ECM components leading to increased resistance of ovarian cancer cells to paclitaxel and topotecan. Expression found in ovarian cancer tissue suggests its possible role in ovarian cancer pathogenesis.
Highlights
The major cause of ovarian cancer treatment failure is tumoral heterogeneity and occurrence of drug resistance in ovarian cancer patients
We observed proportional increase of both transcripts level in investigated cell lines (R2 = 0.998), the expression of Matrix Gla protein (MGP)-201 was higher than MGP-203 in all resistant cell lines; 189- vs. 77-fold for A2780PR1, 155- vs. 43-fold for A2780TR1 and 1098- vs. 428-fold for A2780TR2 cell line
Since MGP is expressed in two main transcript variants corresponding to two protein isoforms with molecular weight of 15.32 kDa (128 aa) (MGP-201) and 12.35 kDa (103 aa) (MGP-203), we compared the expression levels of both MGP transcripts in ovarian cancer drug sensitive and resistant cell lines
Summary
The major cause of ovarian cancer treatment failure is tumoral heterogeneity and occurrence of drug resistance in ovarian cancer patients. There are two mechanisms of inherent or acquired during treatment chemoresistance that involve cellular and/or tissue specific response. The tumor environment is identified as a leading factor that promotes cancer progression and resistance to anticancer therapy [4]. It is composed of cellular (cancer cells, cancer associated fibroblasts (CAFs), and tumor associated macrophages (TAMs)) and non-cellular constituents including extracellular matrix components (ECM). It has been reported that changes in ECM can modulate drug resistance by preventing the penetration of anticancer drugs through tumor tissue [6,7]. Changes in the microenvironment induce tumor progression, malignancy and anticancer drug resistance through integrin signaling as the result of ECM tumor-associated remodeling [8]. The development of drug resistance caused by compounds of extracellular matrix has been described as cell adhesion-mediated drug resistance (CAM-DR) [10] and noted in small cell lung cancer in vivo and in ovarian cancer in vitro [11,12] different molecules of ECM have been described as produced by cultured cells in vitro, e.g., drug resistant breast [13] and ovarian cancer cell lines [14,15]
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