Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

Abstract

Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.

Proteomes of Residual Tumors in Curcumin-Treated Rats Reveal Changes in Microenvironment/Malignant Cell Crosstalk in a Highly Invasive Model of Mesothelioma

“…The parallel decrease in PAK1 also attests to the reduced progression stage of the curcumin-treated tumors, as this effector of the Rho GTPases (encoded by Pak1 ), involved in cell motility and cytoskeleton remodeling, is overexpressed in almost all tumors [ 60 ]. Finally, one last line of evidence of this reduced invasiveness is given by the decrease in the Ena/VASP-like protein (encoded by Evl ), which organizes stress fibers leading to cancer cell stiffening [ 52 ], with stiffness playing an important role in the harmful effects of epithelial-to-mesenchymal transition (EMT) in invasive cancers [ 67 ].…”

“…IRF2BPL is one of three members of a family of transcriptional regulators that potentially control various hallmarks of oncogenesis, including tumor suppression depending on the context [ 79 ]. A recent work has demonstrated that it downregulates Wnt signaling by interacting with and targeting β-catenin (crucial markers of EMT in cancer [ 67 ]) for proteasomal degradation [ 80 ]. The second protein, a member of the hexokinase family encoded by Hk3 , participates in tumor immune microenvironment remodeling and promotes immune escape, with its high expression leading to a poor prognosis in patients with renal carcinoma [ 81 ].…”

Anti-Cancer Potential of Phytochemicals: The Regulation of the Epithelial-Mesenchymal Transition

“…Flavonoids have a variety of positive health effects, such as anti-bacterial, anti-cancer, anti-osteoporosis, and anti-viral functions [44]. In this type of compound, quercetin (4), silybin ( 5), baicalein (6), genistein (10), hesperidin (11), and naringenin (12) have been reported to have EMT inhibitory effects (Figure 4).…”

“…During this process, cells undergo morphological changes associated with the repression of epithelial markers and the acquirement of mesenchymal marker proteins. The most notable marker of epithelial cells is E-cadherin, while N-cadherin is the most representative marker of mesenchymal-type cells [ 12 ]. The switch from E-cadherin to N-cadherin is often used for the identification of EMT processes.…”

“…The structure of this compound belongs to diarylheptanoids. Due to its broad bioactivities, including chemoprevention, anti-cancer, and anti-inflammation, curcumin has attracted much interest and has been proven as an EMT suppressor in many kinds of cancer [ 12 ]. The benefits of inhibiting the EMT process by curcumin in malignant tumors lie mainly in preventing tumor metastasis.…”