Targeting the PI3K/AKT/mTOR signaling pathway as an effectively radiosensitizing strategy for treating human oral squamous cell carcinoma in vitro and in vivo

Abstract

Radiation therapy (RT) is the current standard adjuvant approach for oral squamous cell carcinoma (OSCC) patients. Radioresistance is a major contributor to radiotherapy failure. In this study, we used patient-derived cells and a radiation-resistant cell line in vitro and in vivo for two purposes: evaluate the anti-tumor effects and understand the mechanisms in the dual PI3K/mTOR signaling pathway regulation of radiosensitization. Our findings indicate that in OML1-R cells, the radioresistance phenotype is associated with activation of the PI3K/AKT/mTOR signaling pathway. Compared to a combination of PI3K or mTOR inhibitors and radiation, dual blockade of the PI3K and mTOR kinases significantly improved radiation efficacy in oral cancer and patient-derived OSCC cells. Dual PI3K/mTOR inhibition enhanced the effect of radiation by inhibiting AKT/mTOR signaling pathways and caused G1 phase arrest, which is associated with downregulation of cyclin D1/CDK4 activity, leading to growth inhibition. In nude mice xenografted with radioresistant OML1-R cells, the combined treatment was also more effective than RT alone in reducing tumor growth. This treatment was also demonstrated to be dependent on the inhibition of protein kinase-dependent S6 kinase pathway and eIF4E-mediated cap-dependent translation. These findings indicate that activation of the PI3K/AKT/mTOR signaling pathway has a role in radioresistance of OSCC. We determined that a PI3K/mTOR inhibitor combined with radiation exhibits synergistic inhibition of the AKT/mTOR axis and induces cell cycle arrest. Our results show the therapeutic potential of drugs targeting the PI3K/AKT/mTOR signaling pathway should be new candidate drugs for radiosensitization in radiotherapy.

Photodynamic Therapy Mediated by 5‐aminolevulinic Acid Promotes the Upregulation and Modifies the Intracellular Expression of Surveillance Proteins in Oral Squamous Cell Carcinoma

“…It was expected that the phosphorylation of Akt and mTOR would improve the expression of cyclin D1 since the formation of this protein can be induced through the activation of mTORC1 complex ; in addition, inhibition of the PI3K/Akt/mTOR signaling pathway promoted downregulation of cyclin D1 in oral cancer cells . However, we did not find clear overexpression of cyclin D1 when we compared the control and PDT groups.…”

Ursolic acid induces apoptosis and autophagy in oral cancer cells

“…Drugs targeting Akt/mTOR signaling act as radiosensitizing agents because the overexpression of Akt/mTOR contributes to the malignancy and radioresistance of OSCC cells . p‐Akt, p‐mTOR, and NF‐κB levels are reported to be higher in OSCC tissues than in non‐dysplastic oral tissues .…”

Leptin impairs the therapeutic effect of ionizing radiation in oral squamous cell carcinoma cells

“…Additionally, it was demonstrated that AKT is involved in response to radiation . The activation of the PI3K/AKT/mTOR signaling pathway promoted radioresistance of OSCC . So, this prompted us to think that leptin can reduce the sensitivity of OSCC cells to radiation, increasing the cell proliferation, through upregulation of EEF2 protein.…”