Role of p38 <scp>MAPK</scp> in disease relapse and therapeutic resistance by maintenance of cancer stem cells in head and neck squamous cell carcinoma

Roy, Shomereeta; S, Roy; Kar, Madhabananda; Padhi, Swatishree; Saha, Arka; Anuja, Kumari; Banerjee, Birendranath

doi:10.1111/jop.12707

Cited by 32 publications

(25 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data revealed that CSC_EVs increased CDDP resistance, metastasis, and the self-renewal capability of OSCC CAL27 and SCC-15 cells, with a concomitant increase in expressions of several oncogenic markers such as PI3K, STAT3, mTOR, TGF-β1, and the stemness marker β-catenin, in CAL27 and SCC-15 cells after their coculture with CSC_EVs. These findings are consistent with those of previous studies that demonstrated that enhanced PI3K/mTOR/STAT3 signaling promotes chemoresistance, stemness, and the metastatic potential of oral cancer cells [25,29].…”

Section: Discussionsupporting

confidence: 93%

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Chen

Bamodu

et al. 2019

Cancers

View full text Add to dashboard Cite

Oral squamous cell carcinoma (OSCC) is among the most commonly diagnosed malignancies in the world. Patients with OSCC often develop treatment resistance, resulting in a poor prognosis. Mounting evidence indicates that interactions between cancerous cells and other components of the tumor microenvironment (TME) determine their response to treatment. Herein, we examined the role of cancer stem cell-derived extracellular vesicles (CSC_EVs) generated from CAL27 and SCC-15 OSCC cells in the development of cisplatin (CDDP) resistance. We demonstrated that CSC_EVs enhance CDDP resistance, clonogenicity, and the tumorsphere formation potential of OSCC cells. Our bioinformatics analyses revealed that OSCC_EVs are enriched with microRNA (miR)-21-5p and are associated with increased metastasis, stemness, chemoresistance, and poor survival in patients with OSCC. Mechanistically, enhanced activity of CSC_EVs was positively correlated with upregulated Cancers 2020, 12, 56 2 of 16 β-catenin, phosphatidylinositol-3 kinase (PI3K), signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR), and transforming growth factor (TGF)-β1 messenger (m)RNA and protein expression levels. CSC_EVs also conferred a cancer-associated fibroblast (CAF) phenotype on normal gingival fibroblasts (NGFs), with the resultant CAFs enhancing the oncogenicity of OSCC cells. Interestingly, treatment with ovatodiolide (OV), the bioactive component of Anisomeles indica, suppressed OSCC tumorigenesis by reducing the cargo content of EVs derived from CSCs, suppressing self-renewal, and inhibiting the NGF-CAF transformation by disrupting EV-TME interactions. Moreover, by suppressing miR-21-5p, STAT3, and mTOR expressions in CSC_EVs, OV re-sensitized CSCs to CDDP and suppressed OSCC tumorigenesis. In vivo, treatment with OV alone or in combination with CDDP significantly reduced the tumor sphere-forming ability and decreased EV cargos containing mTOR, PI3K, STAT3, β-catenin, and miR-21-5p. In summary, our findings provide further strong evidence of OV's therapeutic effect in OSCC.

show abstract

Section: Discussionsupporting

confidence: 93%

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Chen

Bamodu

et al. 2019

Cancers

View full text Add to dashboard Cite

show abstract

“…Knockdown of either p38 or HSP27 enhanced cisplatin sensitivity. In head and neck cancer patients, the upregulation of p38 expression and activation in the surgical resection margin of the tumor is associated with the expression of CSC markers (OCT4, KLF4, MYC, and CD44) and a higher frequency of relapse [135]. Treatment of cultured tumor cells with p38 inhibitors reduced the expression of CSC markers and sensitized the cell to DNA damage induction and cisplatin.…”

Section: P38 Enhancing Resistance To Targeted Therapies and Chemothermentioning

confidence: 99%

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Lee

Rauch

Kölch

2020

IJMS

489

338

View full text Add to dashboard Cite

Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.

show abstract

“…Upregulation of p38 promotes CSC-like characteristics in osteosarcoma and breast cancer cells [48, 49]. p38 activity is critical for maintaining CSCs traits in head and neck squamous cell carcinoma [22]. Our previous study indicated that TS induced p38 activation in mouse liver tissues [23].…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of p38 is able to transduce various signals and elicit a wide range of cellular response [21]. Suppression of p38 activity reduced the expression of CSCs markers and sphere formation ability, and decreased migratory potential in head and neck squamous cell carcinoma [22]. Previous study showed that TS triggered MAPK pathways activation in the liver of BALB/c mice [23].…”

Section: Introductionmentioning

confidence: 99%

Tobacco smoke induced hepatic cancer stem cell-like properties through IL-33/p38 pathway

Xie

Zhu

Wang

et al. 2019

J Exp Clin Cancer Res

View full text Add to dashboard Cite

BackgroundTobacco smoke (TS) critically contributes to the development of hepatocellular carcinoma. Cancer stem cells (CSCs) induced by TS is an early event in the initiation of carcinogenesis. Tumor specific microenvironment including inflammatory factors is key mediator for maintaining the stemness of CSCs through various pathways such as p38 MAPK. However, the mechanisms of inflammatory factors in TS-induced acquisition of liver CSCs properties remain undefined. The aim of this study was to investigate the role of IL-33/p38 axis in long term TS-induced acquisition of hepatic CSCs properties in mouse liver tissues and human liver cells.MethodsBALB/c mice were exposed to TS for 12 weeks, along with or without 1 mg/kg SB203580 (p38 inhibitors) treatment. Histopathological analysis, alterations in the levels of IL-33, liver CSCs markers, EMT-like changes and p38 MAPK activation in liver tissues of mice were analyzed by immunohistochemical staining, immunofluorescence assay and Western blot analysis. Moreover, LO2 immortalized human liver cells were exposed to cigarette smoke extract (CSE) and the tumorsphere formation ability was determined. LO2 cells were further treated with IL-33 or CSE and the expression of phosphorylated p38, liver CSCs markers and EMT-related proteins was examined.ResultsLong term TS exposure increased the levels of CSCs markers, induced epithelial-to mesenchymal transition (EMT) and inflammatory factor IL-33 expression. Moreover, we showed that p38 MAPK modulated TS-stimulated hepatic CSC-like properties, as evidenced by the findings that long term TS exposure activated p38, and that TS-induced stemness was abolished by p38 inhibition. In addition, data from in vitro model showed that similar to cigarette smoke extract (CSE), IL-33 treatment promoted the activation of p38, increased the levels of liver CSCs markers expression and EMT-like changes.ConclusionsCollectively, these data suggested that IL-33/p38 axis plays an important role in long term TS exposure-induced acquisition of hepatic CSC-like properties.

show abstract

Role of p38 MAPK in disease relapse and therapeutic resistance by maintenance of cancer stem cells in head and neck squamous cell carcinoma

Abstract: This study demonstrated that p38 MAPK activation may play a role in therapeutic resistance and disease relapse in HNSCC by maintenance of CSCs phenotype.

Cited by 32 publications

References 28 publications

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Tobacco smoke induced hepatic cancer stem cell-like properties through IL-33/p38 pathway

Contact Info

Product

Resources

About