Epithelial‐to‐Mesenchymal Transition in Paclitaxel‐Resistant Ovarian Cancer Cells Is Downregulated by Luteolin

Abstract

Ovarian cancer (OVCA) is the deadliest of all gynecological cancers which is attributed to late presentation, persistence, and development of chemoresistance. The objectives were to evaluate the association between OVCA paclitaxel-resistance and epithelial-to-mesenchymal transition (EMT) and to determine the capability of luteolin to chemosensitize OVCA cells. X10 and X22 cells were 11.8-25.3-fold and 7.8-8.6-fold resistant to paclitaxel than 1AP cells. X10 and X22 cells exhibited a mesenchymal phenotype, while 1AP has an epithelial characteristics. Furthermore, the expression of the epithelial marker E-cadherin was downregulated, while mesenchymal markers Vimentin and N-cadherin were upregulated in X10 and X22 cells when compared to 1AP cells. Transcription factors Snail, Slug, and Twist1 were upregulated in X10 cells, while Twist1 was highly expressed in X22 cells. Luteolin treatment caused cytotoxicity being most potent to X10 OVCA cells. Treatment of non-cytotoxic dose of luteolin at 15.625 μM chemosensitized X10 and X22 OVCA cells to paclitaxel as evidenced by reduced ED values from 11.8 to 0.2 μM and 8.6 to 3.6 μM for X10 and X22 cells, respectively. Moreover, luteolin treatment led to a more epithelial phenotype of X10 and X22 cells and modification of EMT markers indicating reversal of EMT. The mechanism involved is through reduction of phosphorylation of FAK and ERK leading to reduced nuclear translocation of p65. Our results highlight the significance of EMT in OVCA resistance to paclitaxel and warrant the investigation of luteolin as a potential therapeutic agent in chemoresistant OVCA. J. Cell. Physiol. 232: 391-401, 2017. © 2016 Wiley Periodicals, Inc.

Comparison of the Biological and Functional Characteristics of Mesenchymal Stem Cells From Intrahepatic and Identical Bone Marrow

“…An FCM measurement revealed positive for CD90, CD105, and PDGFR-β and negative for CD31 and CD45 indicating that the majority of MLpvNG2 + cells have similar expression patterns to niBM-MSCs [32] . The expressions of mesodermal markers of vimentin, N-cadherin, Col1a1, Prrxl, Snail [33] and the ability to differentiate into mesodermal lineages that are consistent with those of other studies that characterized MSCs derived from multiple sources [34] , indicating that MLpvNG2 + cells originate from a mesenchymal source [35,36] . As oct3/4 is a main marker for embryonic stem cells [37] and its higher expression in MLpvNG2 + cells than in niBM-MSCs might suggest that MLpvNG2 + cells may be more "stem" than niBM-MSCs, needs to be further investigated.…”

Kanglaite inhibits EMT caused by TNF-α via NF-κΒ inhibition in colorectal cancer cells

“…Many epithelial tumors undergo EMT, which facilitates their invasion. Longterm treatment with anti-tumor drugs, such as paclitaxel [ 26 ] and cisplatin [ 27 ], causes tumor resistance and EMT, but some agents can reverse the EMT induced by anti-tumor drugs [ 26 , 27 ]. It has been shown that NF-κΒ activation is one response of tumor cells to some drugs, and that it contributes to EMT [ 8 , 28 ].…”

Luteolin Promotes Cell Apoptosis by Inducing Autophagy in Hepatocellular Carcinoma

“…Plants rich in luteolin have been used in Chinese traditional medicine to treat various diseases, such as hypertension, inflammatory disorders, and cancer [3, 4]. The anti-cancer activities of luteolin have been demonstrated in many cancer cells, such as pancreatic cancer, prostate cancer, breast cancer, colorectal cancer, and ovarian cancer [5-8]. In addition, luteolin could upregulate the mRNA expression level of intercellular adhesion molecule-1, a tumor suppressor gene [9], in mouse H22 hepatoma cells [10].…”