PI3K/AKT/mTOR Dysregulation and Reprogramming Metabolic Pathways in Renal Cancer: Crosstalk with the VHL/HIF Axis

Bădoiu, Silviu Constantin; Greabu, Maria; Miricescu, Daniela; Stănescu-Spînu, Iulia-Ioana; Ilinca, Radu; Bălan, Daniela Gabriela; Balcangiu‐Stroescu, Andra-Elena; Mihai, Doina-Andrada; Văcăroiu, Ileana Adela; Ştefani, Constantin; Jinga, Viorel

doi:10.3390/ijms24098391

Cited by 8 publications

(3 citation statements)

References 242 publications

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“…Much of this is related to upregulation of the hypoxia inducible factor (HIF) pathway due to inactivation of the von Hippel Lindau ( VHL ) tumour suppressor gene. Increased HIF activity leads to activation of several metabolic pathways, including those relevant to glycolysis 41 . In breast cancer cell lines, miR155 has been demonstrated to promote tumour cell growth via altered glucose metabolism, by increasing activity of the phosphoinositide 3-kinases (PI3K)-FOXO3a/c-MYC axis, and reducing glucose transport 4 (GLUT4) expression 42 .…”

Section: Discussionmentioning

confidence: 99%

Circulating microRNA-155-3p levels predicts response to first line immunotherapy in patients with metastatic renal cell carcinoma

Soleimani,

Thi,

Janfaza

et al. 2024

Sci Rep

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Predictive biomarkers of response to immune checkpoint-based therapies (ICI) remain a critically unmet need in the management of advanced renal cell carcinoma (RCC). The complex interplay of the tumour microenvironment (TME) and the circulating immune response has proven to be challenging to decipher. MicroRNAs have gained increasing attention for their role in post-transcriptional gene expression regulation, particularly because they can have immunomodulatory properties. We evaluated the presence of immune-specific extracellular vesicle (EV) microRNAs in the plasma of patients with metastatic RCC (mRCC) prior to initiation of ICI. We found significantly lower levels of microRNA155-3p (miR155) in responders to ICI, when compared to non-responders. This microRNA has unique immunomodulatory properties, thus providing potential biological rationale for our findings. Our results support further work in exploring microRNAs as potential biomarkers of response to immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Circulating microRNA-155-3p levels predicts response to first line immunotherapy in patients with metastatic renal cell carcinoma

Soleimani,

Thi,

Janfaza

et al. 2024

Sci Rep

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“…Figure 2 depicts the well-established signaling pathways of mTOR. The PI3K/AKT/mTOR pathway is of paramount significance in various cancers, such as renal cancer (Badoiu et al, 2023), gastric cancer (Fattahi et al, 2020), ovarian cancer (Ediriweera et al, 2019), non-small-cell lung cancer (Yip, 2015), acute myeloid leukemia (Nepstad et al, 2020), and endometrial cancer (Yunyun Li et al, 2016). Experimental validation has demonstrated the efficacy of the rapalog ridaforolimus in Overview of the signaling pathway that was affected by ridaforolimus.…”

Section: Signaling Pathways That Ridaforolimus Affectedmentioning

confidence: 99%

Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review

Wang,

Qiu,

Yang

et al. 2024

Front. Pharmacol.

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Rapamycin, an established mTOR inhibitor in clinical practice, is widely recognized for its therapeutic efficacy. Ridaforolimus, a non-prodrug rapalog, offers improved aqueous solubility, stability, and affinity compared to rapamycin. In recent years, there has been a surge in clinical trials involving ridaforolimus. We searched PubMed for ridaforolimus over the past decade and selected clinical trials of ridaforolimus to make a summary of the research progress of ridaforolimus in clinical trials. The majority of these trials explored the application of ridaforolimus in treating various tumors, including endometrial cancer, ovarian cancer, prostate cancer, breast cancer, renal cell carcinoma, and other solid tumors. These trials employed diverse drug combinations, incorporating agents such as ponatinib, bicalutamide, dalotuzumab, MK-2206, MK-0752, and taxanes. The outcomes of these trials unveiled the diverse potential applications of ridaforolimus in disease treatment. Our review encompassed analyses of signaling pathways, ridaforolimus as a single therapeutic agent, its compatibility in combination with other drugs, and an assessment of adverse events (AEs). We conclude by recommending further research to advance our understanding of ridaforolimus’s clinical applications.

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“…Indeed, in some model organisms, such as in C. Elegans, Drosophila melanogaster, and in mice, interventions have shown that the suppression of mTOR could expand the maximal life span [15][16][17][18]. Also, the dysregulation of mTOR pathways has been observed in different types of cancers [19,20]. Additionally, some of the drugs used in therapies for cancer inhibit the proliferation of the tumor cells by the mTOR pathway.…”

Section: Introductionmentioning

confidence: 99%

The Impact of 8 Weeks of Combined Physical Exercise Training on SIRT3 and mTOR in Lymphocytes, and on Lipid Peroxidation

Soares,

Cardoso,

Almeida

et al. 2024

Healthcare

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The sirtuins (SIRT) protein family and the mechanistic/mammalian target of rapamycin (mTOR) are intracellular molecules that have been involved in the regulation of several biological processes, as well as in various aging-related processes. This pilot study, in small scale, aimed to analyze the effects of an 8-week physical exercise program on SIRT3 and mTOR levels in lymphocytes, as well as on lipid peroxidation in middle aged and older men. A total of 9 participants aged between 56 and 73 years were enrolled in an 8-week physical exercise program comprising cardiovascular and high-intensity interval training. The program involved three sessions per week, each lasting 45–60 min, conducted on non-consecutive days. Tests were conducted before and after the experimental period (pre- and post-training). Assessments included a vertical jump, 20 m velocity, ball throwing, and an aerobic capacity test. Lipid peroxidation (MDA) was measured in plasma as an oxidative stress biomarker. Additionally, sirtuin 3 (SIRT3/β-actin) and mTOR (mTOR/β-actin) levels were measured in isolated lymphocytes extracted from venous blood. Following the exercise training period, our results demonstrated a significant improvement in aerobic capacity (pre-training: 615.4 ± 45.3 m; post-training: 687.2 ± 34.6 m; t = −2.521; p = 0.012) and 20 m velocity (pre-training: 4.6 ± 0.5 s; post-training: 4.3 ± 0.3 s; t = −2.023; p = 0.04). Concerning blood variables, there was a significant decrease in mTOR levels (pre-training: 0.857 ± 0.593; post-training: 0.214 ± 0.097; t = −2.547; p = 0.011), while no changes were observed in SIRT3 (pre-training: 0.608 ± 0.404; post-training: 0.516 ± 0.390; t = 0.533; p = 0.594) and MDA (pre-training: 8420 ± 4615; post-training: 8800 ± 3163; t = −0.533; p = 0.594). The notable reduction in mTOR levels in lymphocytes following the 8-week physical exercise program suggests a potential role of exercise in modulating immune cell dynamics, particularly in middle-aged and older individuals. Furthermore, the exercise regimen resulted in improvements in physical function, including enhanced aerobic capacity and walking velocity.

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PI3K/AKT/mTOR Dysregulation and Reprogramming Metabolic Pathways in Renal Cancer: Crosstalk with the VHL/HIF Axis

Cited by 8 publications

References 242 publications

Circulating microRNA-155-3p levels predicts response to first line immunotherapy in patients with metastatic renal cell carcinoma

Circulating microRNA-155-3p levels predicts response to first line immunotherapy in patients with metastatic renal cell carcinoma

Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review

The Impact of 8 Weeks of Combined Physical Exercise Training on SIRT3 and mTOR in Lymphocytes, and on Lipid Peroxidation

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