Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer

Li, Huayi; Prever, Lorenzo; Hirsch, Emilio; Gulluni, Federico

doi:10.3390/cancers13143517

Cited by 103 publications

(77 citation statements)

References 169 publications

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“… 31 Due to its critical role in cell metabolism, the PI3K/AKT pathway is intricately linked to multiple diseases, including cardiovascular disease, diabetes, and cancer. 32 , 33 The activation of the PI3K/AKT pathway is essential for maintaining the physiological functions of MSCs; however, it is significantly suppressed under certain pathological situations. Accumulating evidence indicates that activating the PI3K/AKT pathway could protect MSCs from harmful factors and enhance their proliferation, migration, and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway

Li¹,

Wang²

2022

DDDT

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Purpose: High glucose environment in diabetes mellitus induces the dysfunction of bone marrow-derived mesenchymal stromal cells (BMSCs) and impairs bone regeneration. Chrysin is a natural polyphenol with outstanding anti-inflammation and anti-oxidation ability. However, whether and how chrysin affects BMSCs in high glucose conditions remain poorly understood. The present study aimed to explore the effects and underlying mechanisms of chrysin on the BMSCs exposed to high glucose environment. Materials and Methods: Cell viability was detected by cell counting kit 8 assay and 5ethynyl-2'-deoxyuridine staining, while cell apoptosis was determined through flow cytometry using Annexin V-FITC/PI kit. The oxidative stress in BMSCs was evaluated by detecting the reactive oxygen species production, malondialdehyde content, and superoxide dismutase activity. Alkaline phosphatase staining, Alizarin Red staining, and quantitative real-time PCR were performed to determine the osteogenic differentiation. Western blot was used to examine the expression of the PI3K/ATK/Nrf2 signaling pathway. Furthermore, chrysin was injected into calvarial defects of type 1 diabetic SD rats to assess its in vivo bone formation capability. Results: Chrysin reduced oxidative stress, increased cell viability, and promoted osteogenic differentiation in BMSCs exposed to high glucose. Blocking PI3K/ATK/Nrf2 signaling pathway weakened the beneficial effects of chrysin, indicating that chrysin at least partly worked through the PI3K/ATK/Nrf2 pathway. Conclusion: Chrysin can protect BMSCs from high glucose-induced oxidative stress via the activation of the PI3K/AKT/Nrf2 pathway, and promote bone regeneration in type 1 diabetic rats.

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Section: Discussionmentioning

confidence: 99%

Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway

Li¹,

Wang²

2022

DDDT

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“…The presence of five cases without CIP2A overexpression and high p-AKT confirmed our previous observations in the cohort of 220 cases about the existence of other molecular mechanisms distinct fromCIP2A involved in p-AKT regulation in breast cancer. Thus, potential pAKT regulators with previously reported relevance in breast cancer such as PDK1 or PTEN should be investigated in forthcoming studies [ 56 ]. In addition, PP2A directly targets pAKT, and endogenous PP2A inhibitors such as SET havebeen described to be altered in breast cancer and involved in pAKT regulation [ 12 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

CIP2A as a Key Regulator for AKT Phosphorylation Has Partial Impact Determining Clinical Outcome in Breast Cancer

Luque

Cristóbal

Sanz-Álvarez

et al. 2022

JCM

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Together with its reported ability to modulate AKT phosphorylation (p-AKT) status in several tumor types, the oncoprotein CIP2A has been described to induce breast cancer progression and drug resistance. However, the clinical and therapeutic relevance of the CIP2A/AKT interplay in breast cancer remains to be fully clarified. Here, we found high p-AKT levels in 80 out of 220 cases (36.4%), which were associated with negative estrogen receptor expression (p = 0.049) and CIP2A overexpression (p < 0.001). Interestingly, p-AKT determined substantially shorter overall (p = 0.002) and progression-free survival (p = 0.003), and multivariate analyses showed its CIP2A-independent prognostic value. Moreover, its clinical relevance was further confirmed in the triple negative and HER2-positive subgroups after stratifying our series by molecular subtype. Functionally, we confirmed in vitro the role of CIP2A as a regulator of p-AKT levels in breast cancer cell lines, and the importance of the CIP2A/AKT axis was also validated in vivo. Finally, p-AKT also showed a higher predictive value of response to doxorubicin than CIP2A in ex vivo analyses. In conclusion, our findings suggest that CIP2A overexpression is a key contributing event to AKT phosphorylation and highlights the CIP2A/AKT axis as a promising therapeutic target in breast cancer. However, our observations highlight the existence of alternative mechanisms that regulate AKT signaling in a subgroup of breast tumors without altered CIP2A expression that determines its independent value as a marker of poor outcome in this disease.

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“…Salvia rosmarinus extract (RE) significantly suppressed the migration of cultured HGUE-C-1, HT-29 and SW480 cells [ 71 ]; it inhibited migration of HGUE-C-1 cells by 28.8 and 66.1%, respectively, HT-29 cells by 22.1 and 92.5%, respectively and SW480 cells by 5.6 and 76.7%, respectively at concentrations of 30 and 40 μg/ml. In PC-3 cells, RE was shown to inhibit cellular migration by 48% through the reduction in mRNA expression of AKT and mTOR by 27% and 40%, respectively, and their phosphorylation by 70% and 65%, respectively [ 27 ], suggesting that RE inhibit the migration of the cancer cell by modulating PI3K/AKT/mTOR signaling pathway [ 85 ]. This is because PI3K/AKT/mTOR signaling pathway has been implicated in development and progression of many cancer cells [ 86 , 87 , 88 , 89 ], making it a good target for new anticancer agents in pipeline such as coptisin [ 90 ], zingerone [ 91 ], mangiferin [ 92 ], erianin [ 93 ], melatonin [ 94 , 95 ] and rapamycin [ 96 ].…”

Section: Application Of Salvia Species In Cancer P...mentioning

confidence: 99%

Therapeutic benefits of Salvia species: A focus on cancer and viral infection

Ezema

Ezeorba

Aguchem

et al. 2022

Heliyon

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Man is increasingly being faced with many health conditions, including viral infection, some of which increases the risk to cancer. These infectious agents contribute to the large number of persons with cancer and the worrisome number that die from the diseases. A good range of drugs are currently in place for treating patients infected with viruses, however, some of the drugs' effectiveness are limited by the emergence of drug-resistant strains of the viruses, as well as adverse effects of the drugs. Similarly, the inability of many anticancer drugs to selectively kill cancer cells while sparing hosts’ normal cells limit their use. This warrants more research for newer drugs, especially from chemicals naturally encrypted in plants with anticancer and antiviral activities. In response to infection with cancer-inducing viruses, plants such as Salvia species synthesize and store secondary metabolites to protect themselves and kill these viruses as well as inhibit their ability to induce carcinogenesis. Hence, this review presented a discussion on the potential application of Salvia species in the prevention and management of cancer and viral infection. The study also discusses the cellular mechanisms of action of these herbal products against cancer cells and viruses, where available and provided suggestions on future research directions. The study is believed to spur more research on how to exploit Salvia phytochemicals as candidates for the development of nutraceuticals and drugs for managing cancers and viral infection.

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Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer

Cited by 103 publications

References 169 publications

Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway

Chrysin Attenuates High Glucose-Induced BMSC Dysfunction via the Activation of the PI3K/AKT/Nrf2 Signaling Pathway

CIP2A as a Key Regulator for AKT Phosphorylation Has Partial Impact Determining Clinical Outcome in Breast Cancer

Therapeutic benefits of Salvia species: A focus on cancer and viral infection

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