Anlotinib Suppresses Oral Squamous Cell Carcinoma Growth and Metastasis by Targeting the RAS Protein to Inhibit the PI3K/Akt Signalling Pathway

Abstract

Oral squamous cell carcinoma (OSCC) is a malignant tumour originating from the mucosal lining of the oral cavity. Its characteristics include hidden onset, high recurrence, and distant metastasis after operation. At present, clinical treatment usually includes surgery, chemotherapy, radiotherapy, or the joint use of these modalities. Unfortunately, multidrug resistant is one of the important obstacles that causes cancer chemotherapy failure. Anlotinib, which has recently been proven to have good antitumour effects, is a novel multitargeted tyrosine kinase inhibitor. However, there are few studies of the anlotinib-associated mechanism in OSCC and its underlying molecular mechanism. In our study, in vitro models of human oral squamous cell carcinoma HSC-3 cells were used to determine the efficacy of anlotinib. On the one hand, we showed that anlotinib treatment significantly reduced the viability and proliferation of HSC-3 cells and decreased cell migration by inhibiting the activation of the Akt phosphorylation pathway. On the other side, anlotinib inhibited PI3K/Akt/Bad phosphorylation and promoted apoptosis of HSC-3 cells by activating RAS protein expression. In brief, these results indicated that anlotinib had prominent antitumour activity in OSCC, mainly by inhibiting the PI3K/Akt phosphorylation pathway. This work provides evidences and a basic principle for using anlotinib to treat patients with OSCC for clinical research.

Deoxypodophyllotoxin Induces ROS-Mediated Apoptosis by Modulating the PI3K/AKT and p38 MAPK-Dependent Signaling in Oral Squamous Cell Carcinoma

“…The development of OSCC is often related to change in molecular level of the receptor tyrosine kinase (RTK), PI3K/AKT, and p53 pathway, and G1/S cell cycle transition [ 31 - 33 ]. The PI3K family kinases are lipid kinases comprising of the catalytic subunits (p110α, p110β, p110δ and regulatory subunits (p85α, p85β, p55γ, p55α, p50α) and are downstream of RTKs.…”

Treatment of Metastatic Primary Extramammary Paget Disease With Combination Anlotinib and Tislelizumab: A Case Report and Review of the Literature

“…It had been demonstrated that treatment with alpelisib prolonged DFS among patients with PIK3CA-mutated, HER2-negative advanced breast cancer who had received endocrine therapy previously ( 20 ). The tyrosine kinase inhibitor Anlotinib ( 6 ) has multiple targets and exerts its anti-tumor effect by inhibiting PI3K/Akt phosphorylation ( 7 ). In a recent study, Anlotinib mainly inhibited angiogenesis and tissue tumor cell migration by inhibiting c-Kit, VEGFR2, VEGFR3, FGFR1-4, PDGFR α and β, and other targets, thus inhibiting tumor by inhibited PI3K/AKT/Bad phosphorylation and promoted apoptosis of tumor cells by activating RAS protein expression ( 21 , 22 ).…”

“…Patients with metastatic EMPD may be considered for chemotherapy, targeted therapy, or immune checkpoint inhibitors. The tyrosine kinase inhibitor Anlotinib ( 6 ) has multiple targets and exerts its anti-tumor effect by inhibiting PI3K/AKT phosphorylation ( 7 ). Combined targeted therapy and immune checkpoint inhibitors may be appropriate for patients without good performance status.…”

The Multiple Roles of CD147 in the Development and Progression of Oral Squamous Cell Carcinoma: An Overview

“…Because of the latter, the circulating tumor cells could die, and cancer metastasization could thereby be hindered [ 98 , 99 ]. However, upregulated CD147 intensively activates ERK and AKT signaling ( Figure 1 ) [ 61 , 62 , 63 , 64 , 65 ], which ultimately promotes the survival of circulating OSCC cells even in the absence of the sustainment ordinarily provided to them by a solid ECM: in doing so, CD147 favors OSCC metastatization [ 100 , 101 , 102 ].…”

“…In fact, in accordance with the fact that CD147 sparks AKT, which, in turn, provides OSCC cells with a survival signal that renders them resistant to cytotoxic drugs, CD147 antagonists increase OSCC cells’ sensitivity to fluorouracil [ 236 ]. Still, regarding CD147-promoted AKT activation, it must be highlighted that blocking AKT phosphorylation reduces the proliferation of OSCC cells and induces their apoptosis [ 100 , 101 ]. Moreover, AKT antagonists downregulate the expression of CD147 [ 237 ], as well of its targets, including COX-2, IL-6, TNF-α, or MMP-9 [ 238 ].…”