PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Glaviano, Antonino; Foo, Aaron S. C.; Lam, Hiu Y.; Yap, Kenneth C. H.; Jacot, William; Jones, Robert H.; Eng, Huiyan; Nair, Madhumathy G.; Makvandi, Pooyan; Geoerger, Birgit; Kulke, Matthew H.; Baird, Richard D.; Prabhu, Jyothi S.; Carbone, Daniela; Pecoraro, Camilla; Teh, Daniel B. L.; Sethi, Gautam; Cavalieri, Vincenzo; Lin, Kevin H.; Javidi-Sharifi, Nathalie R.; Toska, Eneda; Davids, Matthew S.; Brown, Jennifer R.; Diana, Patrizia; Stebbing, Justin; Fruman, David A.; Kumar, Alan P.

doi:10.1186/s12943-023-01827-6

Cited by 253 publications

(111 citation statements)

References 442 publications

(512 reference statements)

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“…Although we did not find extra downstream signaling pathways that were highly enriched, the changes in transduction may still have an effect on the downstream mTOR signaling pathway (Figure ), which is essential for glycerolipid metabolism, autophagy control, and protein synthesis . Collectively, our results support the idea that changes in this group of signaling mechanisms may contribute to CW formation.…”

Section: Discussionmentioning

confidence: 99%

Multiomics Analysis Unravels Alteration in Molecule and Pathways Involved in Nondiabetic Chronic Wounds

Zeng,

Zheng,

Wei

et al. 2024

ACS Omega

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The prevalence of chronic wounds (CW) continues to grow. A thorough knowledge of the mechanism of CW formation remains elusive due to a lack of relevant studies. Furthermore, most previous studies concentrated on diabetic ulcers with relatively few investigations on other types. We performed this multiomics study to investigate the proteomic and metabolomic changes in wound and surrounding tissue from a cohort containing 13 patients with nondiabetic CW. Differentially expressed proteins (DEPs) and metabolites (DEMs) were filtered out and analyzed through multiomic profiling. The DEPs were further confirmed with the use of parallel reaction monitoring. Compared with the surrounding tissue, there were 82 proteins and 214 metabolites altered significantly in wound tissue. The DEPs were mainly enriched in focal adhesion (FA), extracellular matrix− receptor interaction (ERI), and the PI3K-Akt (PA) signaling pathway. Moreover, the DEMs were significantly enriched in amino sugar and nucleotide sugar metabolism and biosynthesis of nucleotide sugar pathways. In correlation analysis, we discovered that the PA signaling pathway, as well as its upstream and downstream pathways, coenriched some DEPs and DEMs. Additionally, we found that FBLN1, FBLN5, and EFEMP1 (FBLN3) proteins dramatically elevated in wound tissue and connected with the above signaling pathways. This multiomics study found that changes in FA, ERI, and PA signaling pathways had an impact on the cellular activities and functions of wound tissue cells. Additionally, increased expression of those proteins in wound tissue may inhibit vascular and skin cell proliferation and degrade the extracellular matrix, which may be one of the causes of CW formation.

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Section: Discussionmentioning

confidence: 99%

Multiomics Analysis Unravels Alteration in Molecule and Pathways Involved in Nondiabetic Chronic Wounds

Zeng,

Zheng,

Wei

et al. 2024

ACS Omega

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“…In addition, the downstream effectors of AKT/mTOR and EGFR signalling are also correlated to CSC-associated survival and metastasis in several cancers (Glaviano et al, 2023). Studies have also shown that Silibinin-treated colon CSCs decreased the fraction of CD44+ surface markers and prevented the development of spheres by boosting the inactivation of the AKTSer473/mTOR survival pathways, suggesting its role in negatively regulating tumour growth (Wang et al, 2012).…”

Section: Silibinin Targets the Molecular Cellular And Signalling Path...mentioning

confidence: 99%

Unravelling the role of Silibinin in targeting CD44+ cancer stem cells: Therapeutic implications, effective strategies and approaches

Lotia,

Patel,

Patel

et al. 2024

Phytotherapy Research

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CD44+ cancer stem cells (CSCs) are believed to account for drug resistance and tumour recurrence due to their potential to self‐renew and differentiate into heterogeneous lineages. Therefore, efficient treatment strategies targeting and eliminating these CSCs are required. The flavonolignan, Silibinin, has gained immense attention in targeting CD44+ CSCs as it alters functional properties like cell cycle arrest, apoptosis, inhibition of invasion and metastasis and also inhibits a range of molecular pathways. However, its limited bioavailability is a major hurdle in asserting Silibinin as a translational therapeutic agent. Combinatorial therapy of Silibinin with conventional chemotherapeutic drugs is an alternative approach in targeting CD44+ CSCs as it increases the efficacy and reduces the cytotoxicity of chemotherapeutic drugs, thus preventing drug resistance. Certain Silibinin‐conjugated nano‐formulations have also been successfully developed, through which there is improved absorptivity/bioavailability of Silibinin and a decrease in the concentration of therapeutic drugs leading to reduced cytotoxicity. In this review, we summarise the effectiveness of the synergistic therapeutic approach for Silibinin in targeting the molecular mechanisms of CD44+ CSCs and emphasise the potential role of Silibinin as a novel therapeutic agent.

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“…Notably, vascular endothelial cells demonstrate a remarkable capability for rapid proliferation, migration, and differentiation in response to physiological stimuli 25 . VEGF has the ability to activate numerous downstream pathways, such as the PI3K-Akt/mTORC2 route, the PLC-MEK pathway, and the Src-FAK pathway that are responsible for vascular permeability, cellular proliferation and cellular motility 26–28 . Through qPCR we have checked the expression of these VEGF pathway genes upon stabilization of VEGF quadruplex by de novo designed peptides.…”

Section: Introductionmentioning

confidence: 99%

In Silico designed cell-penetrating anti-cancer peptide specifically inhibits VEGF-A expression

Banerjee,

Roy,

Panda

et al. 2024

Preprint

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Vascular Endothelial Growth Factor A (VEGF A), a pluripotent cytokine and angiogenic growth factor mediates the switch to an angiogenic phenotype in cancer cells. The interaction of VEGF A protein with the VEGF receptors (VEGFR 1and VEGFR 2) starts downstream effect that promotes angiogenesis by mediating migration and increasing the permeability of endothelial cells. A cis regulatory elements consisting of a polypurine polypyrimidine tract in the proximal 36-bp region, can participate in the formation of a stable higher order G quadruplex structure (G4) which is essential for VEGF promoter activity. During cancer progression the VEGF A G4 succumbs to cellular pressure and fails to maintain the stable structure. This shifts the balance to form duplex structure thereby increasing the rate of transcription. Earlier research has tried to develop small molecule ligands to target and stabilize G4, however they either lack specificity or non toxicity. Peptide on the other hand are very less studied. Here we used bioinformatics in silico tool to develop peptides which can successfully bind and stabilize the VEGF A G4 while reducing its gene expression. This further alters the expression fate of the VEGF A signalling cascade and prevents angiogenesis in cancer cells. We used high resolution Nuclear magnetic resonance and molecular dynamics simulation to map the chemistry of the interaction while the qPCR and western blot allowed us to check the expression pattern of the molecules of VEGF A signalling cascade. In this investigation, we navigate the complex interplay between peptides and quadruplex structures, unravelling valuable insights that can enhance the crafting of pharmacophores directed at the dynamic quadruplex structure. The outcomes of our study are promising, paving the way for progress in the realms of research, characterization, and optimization of peptides binding to G quadruplexes, with potential implications for therapeutic applications.

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PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Cited by 253 publications

References 442 publications

Multiomics Analysis Unravels Alteration in Molecule and Pathways Involved in Nondiabetic Chronic Wounds

Multiomics Analysis Unravels Alteration in Molecule and Pathways Involved in Nondiabetic Chronic Wounds

Unravelling the role of Silibinin in targeting CD44+ cancer stem cells: Therapeutic implications, effective strategies and approaches

In Silico designed cell-penetrating anti-cancer peptide specifically inhibits VEGF-A expression

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