Targeted disruption of PI3K/Akt/mTOR signaling pathway, via PI3K inhibitors, promotes growth inhibitory effects in oral cancer cells

Abstract INTRODUCTION Tumor Treating Fields (TTFields) therapy is an approved anti-cancer treatment modality applied non-invasively and loco-regionally to the tumor region. TTFields have been demonstrated to extend life, however, most patients do eventually progress. The current study aimed to identify potential molecular mechanisms involved in reduced cellular sensitivity to TTFields. METHODS Cancer cells that exhibit reduced sensitivity to TTFields were generated by continuous long duration application of TTFields (7 or 13 days, depending on the cell line). Changes in cellular signaling pathways were evaluated in ovarian A2780 and glioblastoma U-87 MG cancer cells exposed to long-term relative to short-term (3 or 7 days, depending on the cell line) treatment with TTFields using Luminex multiplex assay followed by Western blot validation. The relevance of the affected pathways was confirmed through evaluation of the response to long-term application of TTFields in combination with pharmacological pathway inhibitors by measuring cell counts, apoptosis, and clonogenicity. Relevant pathway markers in tumor sections from tumor-bearing rats treated with TTFields were examined using immunohistochemistry. RESULTS Continuous long-term application of TTFields reduced cellular sensitivity to TTFields and was accompanied by increased levels of phosphorylated AKT, mTOR and additional proteins from the PI3K/AKT/mTOR signaling pathway. Increased phosphorylation of AKT was also evident in tumor sections from rats treated with TTFields. Concomitant use of TTFields with PI3K inhibitors or PI3K/mTOR dual inhibitors sensitized A2780 cells to long-term TTFields application. CONCLUSION Our study demonstrates that decreased cancer cell sensitivity to long-term TTFields application is mediated by activation of the PI3K/AKT/mTOR signaling pathway and provides a rationale for further examining the potential benefit of combining TTFields with PI3K or PI3K/mTOR dual inhibitors.

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Chaga mushroom extract induces autophagy via the AMPK-mTOR signaling pathway in breast cancer cells

Journal of Ethnopharmacology ◽

10.1016/j.jep.2021.114081 ◽

2021 ◽

pp. 114081

Author(s):

Min-Gu Lee ◽

Yun-Suk Kwon ◽

Kyung-Soo Nam ◽

Seo Yeon Kim ◽

In Hyun Hwang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Breast Cancer Cells ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Mushroom Extract

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ANLN promotes carcinogenesis in oral cancer by regulating the PI3K/mTOR signaling pathway

Head & Face Medicine ◽

10.1186/s13005-021-00269-z ◽

2021 ◽

Vol 17 (1) ◽

Author(s):

Bing Wang ◽

Xiao-li Zhang ◽

Chen-xi Li ◽

Ning-ning Liu ◽

Min Hu ◽

...

Keyword(s):

Oral Cancer ◽

Signaling Pathway ◽

Cell Cycle Progression ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Cell Behaviors ◽

Rnai Technology ◽

Tumor Tissues ◽

Pi3k Signaling Pathway

Abstract Background Oral cancer is a malignant disease that threatenshuman life and greatly reducespatientquality of life. ANLN was reported to promote the progression of cancer. This study aims to investigate the role of ANLNin oral cancer and the underlying molecular mechanism. Methods ANLN expression was downregulated by RNAi technology. The effect of ANLN on cell behaviors, including proliferation, cell cycle progression, invasion, and apoptosis, was detected. Western blotting analysis was used to explore the mechanism by whichANLN functions in oral cancer. Results Data from TCGA database showed that ANLN was expressed at significantly higher levels in tumor tissues thanin normal control tissues. Patients with higher ANLN expression exhibitedshorter survivaltimes. ANLN was alsoabundantly expressedin the cancer cell lines CAL27 and HN30. When ANLN was knocked down in CAL27 and HN30 cells, cell proliferation and colony formation weredecreased. The cell invasion ability was also inhibited. However, the cell apoptosis rate was increased. In addition, the levels of critical members of the PI3K signaling pathway, includingPI3K, mTOR, Akt, and PDK-1, were significantlyreducedafter ANLN was knocked down in CAL27 cells. Conclusions ANLN contributes to oral cancerprogressionand affects activation ofthe PI3K/mTOR signaling pathway. This study providesa new potential targetfor drug development and treatment in oral cancer.

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