Transgelin 2 Promotes Paclitaxel Resistance, Migration, and Invasion of Breast Cancer by Directly Interacting with PTEN and Activating PI3K/Akt/GSK-3β Pathway

Abstract

MDR and tumor migration and invasion are still the main obstacles to effective breast cancer chemotherapies. Transgelin 2 has recently been shown to induce drug resistance, tumor migration, and invasion. The aim of this study was to determine the biological functions of Transgelin 2 and the mechanism underlying how Transgelin 2 induces paclitaxel (PTX) resistance and the migration and invasion of breast cancer. We detected that the protein level of Transgelin 2 was significantly upregulated in breast cancer tissues compared with adjacent nontumor tissues. A bioinformatics analysis indicated that Transgelin 2 was significantly related to clinicopathologic parameters and patient prognosis. Overexpression of Transgelin 2 enhanced the migration and invasion of human breast cancer cells and decreased the sensitivity of breast cancer cells to paclitaxel. Meanwhile, the tumorigenesis and metastasis of breast cancer cells were also enhanced by Transgelin 2 overexpression in vivo. Moreover, Transgelin 2 overexpression activated the PI3K/Akt/GSK-3b pathway by increasing the phosphorylation levels of Akt and GSK-3b and decreasing the expression of PTEN. We also found that Transgelin 2 could directly interact with PTEN and was located upstream of PTEN. Furthermore, the PI3K/Akt pathway inhibitor MK-2206 reversed the resistance to paclitaxel and inhibited the migration and invasion of breast cancer cells. These findings indicate that Transgelin 2 promotes paclitaxel resistance and the migration and invasion of breast cancer by directly interacting with PTEN and activating the PI3K/Akt/GSK-3b pathway. Transgelin 2 may therefore be useful as a novel biomarker and therapeutic target for breast cancer.

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

“…Impediments to apoptosis, reducing drug accumulation, alterations in cell cycle and enhancement of the tumor energy supply are the main reasons for MDR. Increases in DNA repair capacity, checkpoint changes, the presence of CSCs in tumors, gene mutations (PTEN mutations or disappearance, mutations in the TP53 gene), changes in drug target separation and epithelial-mesenchymal transition are also related to MDR [133][134][135] . These mechanisms must be carefully discussed in the future.…”

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…Additionally, PRLR/Jak2/STAT5 is the main signaling pathway for activation in mammary gland, and PRLR-triggered pro-tumorigenic pathways in BC include the PI3K/AKT pathway [172]. As well, numerous studies have shown that IRS4, CDK12, SPC24, Mfng, Transgelin 2, STX3, SOX4, PAK4, TPX2, MEG3 and miR-21, -93, -106b, -130b, -214, -361-5p, -489, -511, -564 as well as lncRNA-HOTAIR and MALAT1 regulate tumorigenesis, proliferation, apoptosis, invasion, migration, paclitaxel resistance or anti-Her2 therapy (trastuzumab) resistance of BC cells through PI3K/AKT pathway [173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191]. And then, PI3K/AKT inhibitors have gained wide attentions, and a large number of clinical trials may have provided tremendous promises in the treatment of BC patients (shown in Tables 2 and 3).…”

Long noncoding RNA lncARSR confers resistance to Adriamycin and promotes osteosarcoma progression

“…For example, hypoxia-activated AKT led to overexpression of MRP1 in hepatocellular carcinoma 33 . Transgelin2 motivated AKT and enhanced MRP1 via GSK-3β-dependent pathways in breast cancer 34 . Aberrant expression of glucose transporter 1 enhanced phosphorylation of AKT and promoted Survivin expression, inducing chemoresistance of triplicate-negative breast cancer 35 .…”