The multifaceted role of STAT3 pathway and its implication as a potential therapeutic target in oral cancer

Khatoon, Elina; Hegde, Mangala; Kumar, Aviral; Daimary, Uzini Devi; Sethi, Gautam; Bishayee, Anupam; Kunnumakkara, Ajaikumar B.

doi:10.1007/s12272-022-01398-y

Cited by 9 publications

(9 citation statements)

References 247 publications

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“…Studies over the years have reported that multiple proteins including Bcl-2, caspases, COX-2, matrix metalloproteinases (MMPs), survivin, and vascular endothelial growth factor (VEGF) and cell signaling pathways such as Akt/mTOR and signal transducer and activator of transcription 3 (STAT-3) are pivotal in governing various hallmarks of cancer, such as evasion of apoptosis, cell survival, proliferation, invasion, angiogenesis, and migration. , Abnormal expression of these proteins has been associated with the development and progression of various cancers, including OSCC. ,, …”

Section: Resultsmentioning

confidence: 99%

“…64,65 Abnormal expression of these proteins has been associated with the development and progression of various cancers, including OSCC. 2,66,67 Bcl-2 is an antiapoptotic protein, and it was found to be overexpressed in OSCC. It was also reported that a diminished level of this protein was associated with a higher survival rate of OSCC patients, and thus, it could be considered a predictor of tumor behavior.…”

Section: Effect Of Aa2 and Aa3 On The Migration Of Oscc Cellsmentioning

confidence: 99%

“…85 STAT-3 activation in OSCC leads to cancer cell survival, proliferation, invasion, epithelial-to-mesenchymal transition (EMT), metastasis, immunosuppression, chemoresistance, and poor prognosis. 67 Recent studies have demonstrated the overexpression and constitutive activation of STAT-3 in OSCC, elucidating its pivotal role in driving OSCC aggressiveness. It was also reported that therapeutic strategies targeting STAT-3 led to a reduction in the growth of OSCC cells in vitro.…”

Section: Effect Of Aa2 and Aa3 On The Migration Of Oscc Cellsmentioning

confidence: 99%

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Natural Prenylflavones from the Stem Bark of Artocarpus altilis: Promising Anticancer Agents for Oral Squamous Cell Carcinoma Targeting the Akt/mTOR/STAT-3 Signaling Pathway

Aswathy,

Parama,

Hegde

et al. 2024

ACS Omega

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Artonin E (AA2) and artobiloxanthone (AA3) were extracted and purified from the acetone extract of the stem bark of Artocarpus altilis (Parkinson) Fosberg. Preliminary investigations of both candidates revealed promising cytotoxic effects in oral cancer cells. Moreover, these candidates modulated the expression of pivotal proteins linked to oral cancer progression, eliciting apoptosis through caspase-3 and caspase-9 activation. Additionally, our results showed that AA2 and AA3 suppressed several proteins linked with oral cancer, such as Bcl-2, COX-2, VEGF, and MMP-9, and modulated the cell signaling pathways, such as Akt/mTOR and STAT-3, offering valuable insights into the underlying mechanism of action of these compounds. These findings were robustly validated in silico using molecular docking and molecular dynamic simulations. To our knowledge, these findings have not been previously reported, and the continued exploration and development of these natural products may offer a potential avenue for the effective management of this malignancy.

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Section: Resultsmentioning

confidence: 99%

Section: Effect Of Aa2 and Aa3 On The Migration Of Oscc Cellsmentioning

confidence: 99%

Section: Effect Of Aa2 and Aa3 On The Migration Of Oscc Cellsmentioning

confidence: 99%

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Natural Prenylflavones from the Stem Bark of Artocarpus altilis: Promising Anticancer Agents for Oral Squamous Cell Carcinoma Targeting the Akt/mTOR/STAT-3 Signaling Pathway

Aswathy,

Parama,

Hegde

et al. 2024

ACS Omega

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“…We also noted that the inhibition of proliferation by the peptide seemed to not be striking compared to Akt phosphorylation inhibition. This may be because the cellular proliferation of the HNSCC cells is driven by Akt as well as other signaling pathways such as epidermal growth factor receptor (EGFR) [ 59 ] and signal transducer and activator of transcription 3 (STAT3) [ 60 ]. Moreover, Akt is activated by the mammalian target of rapamycin (mTOR), which is activated by certain signaling molecules other than DKK3.…”

Section: Discussionmentioning

confidence: 99%

Establishment of anti-DKK3 peptide for the cancer control in head and neck squamous cell carcinoma (HNSCC)

et al. 2022

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Background Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of the head and neck. We identified cancer-specific genes in HNSCC and focused on DKK3 expression. DKK3 gene codes two isoforms of proteins (secreted and non-secreted) with two distinct cysteine rich domains (CRDs). It is reported that DKK3 functions as a negative regulator of oncogenic Wnt signaling and, is therefore, considered to be a tumor suppressor gene. However, our series of studies have demonstrated that DKK3 expression is specifically high in HNSCC tissues and cells, and that DKK3 might determine the malignant potentials of HNSCC cells via the activation of Akt. Further analyses strongly suggested that both secreted DKK3 and non-secreted DKK3 could activate Akt signaling in discrete ways, and consequently exert tumor promoting effects. We hypothesized that DKK3 might be a specific druggable target, and it is necessary to establish a DKK3 inhibitor that can inhibit both secreted and non-secreted isoforms of DKK3. Methods Using inverse polymerase chain reaction, we generated mutant expression plasmids that express DKK3 without CRD1, CRD2, or both CRD1 and CRD2 (DKK3ΔC1, DKK3ΔC2, and DKK3ΔC1ΔC2, respectively). These plasmids were then transfected into HNSCC-derived cells to determine the domain responsible for DKK3-mediated Akt activation. We designed antisense peptides using the MIMETEC program, targeting DKK3-specific amino acid sequences within CRD1 and CRD2. The structural models for peptides and DKK3 were generated using Raptor X, and then a docking simulation was performed using CluPro2. Afterward, the best set of the peptides was applied into HNSCC-derived cells, and the effects on Akt phosphorylation, cellular proliferation, invasion, and migration were assessed. We also investigated the therapeutic effects of the peptides in the xenograft models. Results Transfection of mutant expression plasmids and subsequent functional analyses revealed that it is necessary to delete both CRD1 and CRD2 to inhibit Akt activation and inhibition of proliferation, migration, and invasion. The inhibitory peptides for CRD1 and CRD2 of DKK3 significantly reduced the phosphorylation of Akt, and consequently suppressed cellular proliferation, migration, invasion and in vivo tumor growth at very low doses. Conclusions This inhibitory peptide represents a promising new therapeutic strategy for HNSCC treatment.

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“…By triggering the expression of designated matrixins 1, 2, 9, and 10, STAT3 also facilitates cellular infiltration and proliferation ( Zhu et al, 2012 ). HNSCC has been associated with enhanced EGFR transmission, STAT3 stimulation, and upregulation ( Khatoon et al, 2022 ). Moreover, STAT3 was found to be an Src-based activator of EGFR-triggered development of HNSCC in-vitro , inhibiting the apoptotic pathway and accelerating malignant progression in-vivo ( Qureshy et al, 2022 ).…”

Section: Molecular Signaling Cascades Associated With Hnsccmentioning

confidence: 99%

Pharmacological impact of microRNAs in head and neck squamous cell carcinoma: Prevailing insights on molecular pathways, diagnosis, and nanomedicine treatment

Bhattacharjee¹,

Syeda

Rynjah³

et al. 2023

Front. Pharmacol.

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Head and neck squamous cell carcinoma is a disease that most commonly produce tumours from the lining of the epithelial cells of the lips, larynx, nasopharynx, mouth, or oro-pharynx. It is one of the most deadly forms of cancer. About one to two percent of all neo-plasm-related deaths are attributed to head and neck squamous cell carcinoma, which is responsible for about six percent of all cancers. MicroRNAs play a critical role in cell proliferation, differentiation, tumorigenesis, stress response, triggering apoptosis, and other physiological process. MicroRNAs regulate gene expression and provide new diagnostic, prognostic, and therapeutic options for head and neck squamous cell carcinoma. In this work, the role of molecular signaling pathways related to head and neck squamous cell carcinoma is emphasized. We also provide an overview of MicroRNA downregulation and overexpression and its role as a diagnostic and prognostic marker in head and neck squamous cell carcinoma. In recent years, MicroRNA nano-based therapies for head and neck squamous cell carcinoma have been explored. In addition, nanotechnology-based alternatives have been discussed as a promising strategy in exploring therapeutic paradigms aimed at improving the efficacy of conventional cytotoxic chemotherapeutic agents against head and neck squamous cell carcinoma and attenuating their cytotoxicity. This article also provides information on ongoing and recently completed clinical trials for therapies based on nanotechnology.

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The multifaceted role of STAT3 pathway and its implication as a potential therapeutic target in oral cancer

Cited by 9 publications

References 247 publications

Natural Prenylflavones from the Stem Bark of Artocarpus altilis: Promising Anticancer Agents for Oral Squamous Cell Carcinoma Targeting the Akt/mTOR/STAT-3 Signaling Pathway

Natural Prenylflavones from the Stem Bark of Artocarpus altilis: Promising Anticancer Agents for Oral Squamous Cell Carcinoma Targeting the Akt/mTOR/STAT-3 Signaling Pathway

Establishment of anti-DKK3 peptide for the cancer control in head and neck squamous cell carcinoma (HNSCC)

Pharmacological impact of microRNAs in head and neck squamous cell carcinoma: Prevailing insights on molecular pathways, diagnosis, and nanomedicine treatment

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