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Review
. 2021 Jun 16;11(6):893.
doi: 10.3390/biom11060893.

Overview of Evidence-Based Chemotherapy for Oral Cancer: Focus on Drug Resistance Related to the Epithelial-Mesenchymal Transition

Jingjing Sha  1 , Yunpeng Bai  1 , Huy Xuan Ngo  1 , Tatsuo Okui  1 , Takahiro Kanno  1
Affiliations
Review

Overview of Evidence-Based Chemotherapy for Oral Cancer: Focus on Drug Resistance Related to the Epithelial-Mesenchymal Transition

Jingjing Sha et al. Biomolecules. .

Abstract

The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer (OC). Epithelial-mesenchymal transition (EMT) has attracted a great deal of attention in recent years with regard to its relation to the mechanism of chemotherapy drug resistance. EMT-activating transcription factors (EMT-ATFs), such as Snail, TWIST, and ZEB, can activate several different molecular pathways, e.g., PI3K/AKT, NF-κB, and TGF-β. In contrast, the activated oncological signal pathways provide reciprocal feedback that affects the expression of EMT-ATFs, resulting in a peritumoral extracellular environment conducive to cancer cell survival and evasion of the immune system, leading to resistance to multiple chemotherapeutic agents. We present an overview of evidence-based chemotherapy for OC treatment based on the National Comprehensive Cancer Network (NCCN) Chemotherapy Order Templates. We focus on the molecular pathways involved in drug resistance related to the EMT and highlight the signal pathways and transcription factors that may be important for EMT-regulated drug resistance. Rapid progress in antitumor regimens, together with the application of powerful techniques such as high-throughput screening and microRNA technology, will facilitate the development of therapeutic strategies to augment chemotherapy.

Keywords: EMT; chemoresistance; chemotherapy; oral squamous cell carcinoma.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Binding of EMT-AFTs, such as Snail, TWIST, and ZEB1, to E-boxes in the promoter suppresses E-cadherin gene expression, which is the hallmark of EMT. The cells then acquire mesenchymal features and migration capability, and even the stem-cell-like features of the so-called cancer stem cells (CSCs). Moreover, several complex signaling pathways, such as the PI3K/AKT pathway, TGF-β pathway, Notch pathway, etc., participate in regulating the expression of EMT-AFTs, forming a feedforward loop that promotes the EMT process [26,27].
Figure 2
Figure 2
A diagram of the NF-κB (canonical), PI3K/AKT, and TGF-β pathways. NF-κB is shown in the figure as a heterodimer consisting of p65 and p50 subunits. In the canonical pathway, NF-κB is bound and inhibited by IκBα proteins. Binding of proinflammatory cytokines, such as TNF-α, to specific transmembrane receptors activates the IKKβ protein, which phosphorylates IκBα and leads to its ubiquitination and, finally, to proteasomal degradation. In this process, ROS interact with NF-κB in various ways, such as by activating IKKβ or IκBα phosphorylation. The active NF-κB complex translocates to the nucleus. For optimal activation of the transcription of NF-κB for certain target genes, interaction with CBP or p300 is required [137,138]. PI3K consists of two domains, p110 and p85, but its activation requires adapter molecules, such as IRS1. Following activation and phosphorylation of the tyrosine kinase receptor (TKR) by growth factors, TKR will recruit PI3K, finally activating AKT by recruiting phosphoinositide-dependent kinase-1 (PDK1) to the kinase domain of AKT. AKT can subsequently affect downstream factors and activate mTORC1, thereby activating the entire pathway and regulating cell growth and apoptosis. AKT can also be activated by p38, which is controlled by the TGF-β pathway. Activated AKT inhibits IκBα and miR-200, while triggering IKKβ protein to further affect cell immunity, apoptosis, and proliferation [139]. In the TGF-β pathway, members of the TGF-β superfamily, such as TGF-β1, bind to the transmembrane receptor (TGF-β-R), resulting in phosphorylation of the cytoplasmic signaling molecules Smad2 and Smad3. The activated Smad2/3 bind to the signaling transducer, Smad4, and this newly formed complex translocates to the nucleus [140]. There is a great deal of crosstalk between these signaling pathways, and the translocation process can also be inhibited by peroxisome proliferator-activated receptor-γ (PPAR-γ), PTEN, or caspase-3. However, once the functions of the suppressors are inhibited, transcription factors, such as ZEB, vimentin, etc., will be activated and secreted into the extracellular environment, eventually leading to conversion of the microenvironment. p: phosphorylation, u: ubiquitination.
Figure 3
Figure 3
Variation of intra/extracellular factors during the EMT process. These expression changes underlie chemotherapeutic drug resistance. +: up-regulation, -: down-regulation.
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