Suppression of a cancer stem-like phenotype mediated by alpha-lipoic acid in human lung cancer cells through down-regulation of β-catenin and Oct-4

Phiboonchaiyanan, Preeyaporn Plaimee; Chanvorachote, Pithi

doi:10.1007/s13402-017-0339-3

Cited by 27 publications

(36 citation statements)

References 34 publications

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“…It reduced the phenotype of lung CSCs such as anchorageindependent growth and three dimensional sphere formations by diminution of the cellular proteins β-catenin and Oct-4. This was achieved by affecting the amount of active (phosphorylated) Akt (74). Thus Oct-4 could be a potential and novel target for enhancing the treatment of lung cancer.…”

Section: Therapeutic Approaches With Lung Cscsmentioning

confidence: 99%

Lung cancer stem cells—origin, characteristics and therapy

Prabavathy¹,

Swarnalatha²,

Ramadoss³

2018

Stem Cell Investig.

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Section: Therapeutic Approaches With Lung Cscsmentioning

confidence: 99%

Lung cancer stem cells—origin, characteristics and therapy

Prabavathy¹,

Swarnalatha²,

Ramadoss³

2018

Stem Cell Investig.

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“…When patients receive anti-cancer therapies most tumor cells are usually killed, but subpopulations of cancer cells that are resistant to the treatment may remain and give rise to relapse. This phenomenon is thought to be due to the presence of CSCs [ 29 – 31 ]. Therefore, we first performed a sphere formation assay to test the ability of the OE-19 cell line to form putative CSC-derived spheres.…”

Section: Resultsmentioning

confidence: 99%

Drug-induced expression of EpCAM contributes to therapy resistance in esophageal adenocarcinoma

et al. 2018

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BackgroundWith a less than 5% overall survival rate, esophageal adenocarcinoma (EAC) is one of the leading causes of death in the United States. Epithelial cell adhesion molecule (EpCAM) is a cancer stem cell (CSC) marker that is expressed in various epithelial carcinomas, including EAC. Accumulating evidence indicates that CSC subpopulations can initiate cancer development and, in addition, drive metastasis, recurrence and drug resistance. It has also been reported that EpCAM up-regulation in EAC may lead to an aggressive behavior and, thus, an adverse clinical outcome. Here, we aimed to determine whether treatment with standard chemotherapeutic agents may induce EpCAM expression and, concomitantly, increases in malignant potential and drug resistance in EAC.MethodsEpCAM expression was assessed in 20 primary human EAC/adjacent normal tissues, as well as in a human EAC-derived cell line (OE-19), in a pre-malignant Barrett’s Esophagus cell line (Bar-T) and in a benign esophageal cell line (HET 1-A), using immunohistochemistry, Western blotting and qRT-PCR, respectively. Drug-induced resistance was investigated in OE-19-derived spheres treated with (a combination of) adriamycin, cisplatin and 5-fluorouracil (ACF) using survival, adhesion and flow cytometric assays, respectively, and compared to drug resistance induced by standard chemotherapeutic agents (CTA). Finally, ACF treatment-surviving cells were evaluated for their tumor forming capacities both in vitro and in vivo using spheroid formation and xenograft assays, respectively.ResultsHigh EpCAM expression was observed in esophageal cancer tissues and esophageal cancer-derived cell lines, but not in adjacent benign esophageal epithelia and benign esophageal cell lines (HET 1-A and Bar-T). The OE-19 cell spheres were drug resistant and EpCAM expression was significantly induced in the OE-19 cell spheres compared to the non-sphere OE-19 cells. When OE-19 cell spheres were challenged with ACF, the EpCAM mRNA and protein levels were further up-regulated up to 48 h, whereas a decreased EpCAM expression was observed at 72 h. EpCAM down-regulation by RNA interference increased the ACF efficacy to kill OE-19 cells. Increased EpCAM expression coincided with the CSC marker CD90 and was associated with an aggressive growth pattern of OE-19 cell spheres in vivo.ConclusionsFrom our data we conclude that an ACF-induced increase in EpCAM expression reflects the selection of a CSC subpopulation that underlies tumor development and drug resistance in EAC.

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“…Certain members of the homeobox superfamily have been implicated in normal development as well as in the pathological development of cancer. OCT-4 is a homeobox gene well known for its function in generating induced pluripotent stem cells (Bhartiya, 2013;Seiler et al, 2011); this gene has also been identified as an oncogene known for promoting the features of cancer stem cells (Li et al, 2017;Phiboonchaiyanan & Chanvorachote, 2017). In addition to OCT-4, an increasing body of evidence reveals that homeobox genes may participate in the promotion of various malignant phenotypes such as the proliferation, migration and invasion of cancers (Hirao et al, 2019;Miwa & Kanda, 2019;Rodini et al, 2012;Song et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Engrailed-2 promotes a malignant phenotype of esophageal squamous cell carcinoma through upregulating the expression of pro-oncogenic genes

Cao

Wang

Tang

et al. 2020

PeerJ

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Background A number of homeobox genes have been implicated in the development of various cancers. However, the role of engrailed 2 (EN2), a member of the homeobox gene superfamily, in esophageal squamous cell carcinoma (ESCC) remains unknown. Methods The expression of EN2 was examined using quantitative real-time PCR and immunohistochemistry. A stable cell line was established to express exogenous EN2 using a lentivirus system. The malignant phenotype was analyzed with proliferation, clonogenicity, wound-healing and invasion assays. The CRISPR/Cas9 system was adopted to deplete endogenous EN2. RNA profiling was performed using gene expression microarray. The ShRNA-mediated method was used to knock down the expression of SPARC. The structure-function relationship was determined using site-directed mutagenesis. Results EN2 is highly expressed in ESCC. The malignant phenotype of the ESCC cell line was amplified by an overexpression of EN2 but was attenuated by a disruption of EN2. RNA profiling analysis revealed that distinct sets of genes were modulated by the expression of EN2 in various ESCC cell lines and oncogenes were among these. EN2 greatly increased the expression of SPARC in Eca109. Site-directed mutagenesis revealed that the induction of SPARC was closely correlated with the protumor function of EN2. ShRNA-mediated knockdown of SPARC attenuated the malignant phenotype of EN2-infected cells. These data suggest that SPARC is crucial for mediating the protumor function of EN2. Discussion EN2 has an oncogenic function in ESCC that is mediated by upregulating the expression of pro-oncogenic genes downstream. EN2 may potentially act as a diagnostic marker or therapeutic target for ESCC treatment in the future.

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Suppression of a cancer stem-like phenotype mediated by alpha-lipoic acid in human lung cancer cells through down-regulation of β-catenin and Oct-4

Abstract: Our data are indicative for a novel regulatory role and underlying mechanism of LA in the negative regulation of a CSC-like phenotype in non-small cell lung cancer-derived cells.

Cited by 27 publications

References 34 publications

Lung cancer stem cells—origin, characteristics and therapy

Lung cancer stem cells—origin, characteristics and therapy

Drug-induced expression of EpCAM contributes to therapy resistance in esophageal adenocarcinoma

Engrailed-2 promotes a malignant phenotype of esophageal squamous cell carcinoma through upregulating the expression of pro-oncogenic genes

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