PI3K/Akt/mTOR Intracellular Pathway and Breast Cancer: Factors, Mechanism and Regulation

Sharma, Var Ruchi; Gupta, Girish Kumar; Sharma, Anil Kumar; Batra, Navneet; Sharma, Daljit K.; Joshi, Amit

doi:10.2174/1381612823666161116125218

Cited by 109 publications

(78 citation statements)

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“…Knocking out or inhibiting PTEN has been reported to be able to induce the regenerative abilities of multiple neuronal populations such as corticospinal neurons, dorsal root ganglion, retinal ganglion cells and sensory neurons [37][38][39]. In addition, PTEN also functions as an inhibitor to AKT/mTOR pathway [40], which plays an important role in cell proliferation and survival [41,42]. In AKT/mTOR pathway, phosphoinositide 3-kinases (PI3Ks) convert phosphatidylinositol (4,5)-bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3), subsequently activates Akt, mTOR and ribosomal protein (S6), ultimately realizing its neuroprotective effects [43].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-92a-3p enhances functional recovery and suppresses apoptosis after spinal cord injury via targeting phosphatase and tensin homolog

Wang

et al. 2020

Bioscience Reports

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Spinal cord injury (SCI) is a neurological disease commonly caused by traumatic events on spinal cords. MiRNA-92a-3p is reported to be down-regulated after SCI. Our study investigated the effects of up-regulated miR-92a-3p on SCI and the underlying mechanisms. SCI mice model was established to evaluate the functional recovery of hindlimbs of mice through open-field locomotion and scored by Basso, Beattie, and Bresnahan (BBB) locomotion scale. Apoptosis of spinal cord cells was determined by flow cytometry. The effects of miR-92a-3p on SCI were detected by intrathecally injecting miR-92a-3p agomiR (agomiR-92) into the mice prior to the establishment of SCI. Phosphatase and tensin homolog (PTEN) was predicted as a target of miR-29a-3p by TargetScan. We further assessed the effects of agomiR-92 or/and overexpressed PTEN on apoptosis rates and apoptotic protein expressions in SCI mice. Moreover, the activation of protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling was determined by Western blot. The results showed that compared with the sham-operated mice, SCI mice had much lower BBB scores, and theapoptosis rate of spinal cord cells was significantly increased. After SCI, the expression of miR-92a-3p was down-regulated, and increased expression of miR-92a-3p induced by agomiR-92 further significantly increased the BBB score and decreased apoptosis. PTEN was specifically targeted by miR-92a-3p. In addition, the phosphorylation levels of Akt and mTOR were up-regulated under the treatment of agomiR-92. Our data demonstrated that the neuroprotective effects of miR-92a-3p on spinal cord safter SCI were highly associated with the activation of the PTEN/AKT/mTOR pathway.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-92a-3p enhances functional recovery and suppresses apoptosis after spinal cord injury via targeting phosphatase and tensin homolog

Wang

et al. 2020

Bioscience Reports

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“…mTOR forms two distinct complexes with either raptor (mTORC1) or rictor (mTORC2). mTORC1 acts downstream of the Akt signaling pathway, which is deregulated in approximately 60% of breast cancers and plays critical roles in breast cancer development, progression and resistance to chemotherapeutic drugs [2][3][4][5][6][7][8][9][10][11]. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) [12].…”

Section: Introductionmentioning

confidence: 99%

Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer

Sridharan

Basu

2020

IJMS

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The mechanistic target of rapamycin (mTOR) is a master regulator of protein translation, metabolism, cell growth and proliferation. It forms two complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is frequently deregulated in many cancers, including breast cancer, and is an important target for cancer therapy. The immunosuppressant drug rapamycin and its analogs that inhibit mTOR are currently being evaluated for their potential as anti-cancer agents, albeit with limited efficacy. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinases (S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). There are two homologs of S6K: S6K1 and S6K2. Most of the earlier studies focused on S6K1 rather than S6K2. Because of their high degree of structural homology, it was generally believed that they behave similarly. Recent studies suggest that while they may share some functions, they may also exhibit distinct or even opposite functions. Both homologs have been implicated in breast cancer, although how they contribute to breast cancer may differ. The purpose of this review article is to compare and contrast the expression, structure, regulation and function of these two S6K homologs in breast cancer.Most of the earlier studies focused on p70 S6K1 or S6K1 as the downstream target of mTORC1. It was believed that due to structural similarities, S6K1 and S6K2 share redundant functions. Recent studies, however, challenge this notion [21][22][23][24][25]. Both homologs have been implicated in breast cancer, although they may play distinct roles [26,27]. In this review article, we briefly describe differences in structural aspects, regulation and cellular functions of these two homologs prior to discussing their distinct roles in breast cancer. Structure of S6KsBoth S6K1 and S6K2 exhibit a modular structure consisting of an N-terminal regulatory region, the kinase domain, followed by the kinase extension domain and a C-terminal regulatory region harboring the autoinhibitory/pseudosubstrate domain (Figure 1). While they share over 80% homology in the amino acid sequence of their kinase domains, as well as a high degree of similarity in the adjacent kinase extension and pseudosubstrate or autoinhibitory domains with conserved sites critical for their activation [16,17], important differences exist in the extreme N-and C-terminal regions. S6K1 possesses a C-terminal PDZ-binding domain, which promotes association with the actin cytoskeleton [28], whereas S6K2 but not S6K1 harbors a functional nuclear localization signal (NLS) and a proline-rich domain, which may promote interaction with the SH3-domain containing proteins at its C-terminus [16] (Figure 1). It is believed that these key differences between S6K1 and S6K2 will result in differential localization and binding partners and hence distinct functions for the two proteins [21].

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“…In addition, based on the UCA1 expression of gastric cancer cells, we constructed overexpression systems and used silencing lentivirus vectors to investigate the biological function of UCA1 in vitro and in vivo. The PI3K-Akt-mTOR signaling pathway, which is usually abnormal in many human cancers such as pancreatic cancer, colon cancer, breast cancer, and lung cancer [15][16][17][18], was identified as a direct target. Furthermore, our previous studies using microarray screening and bioinformatics analyses to construct the lncRNA-mRNA co-expression network [10], showed that some of the gastric cancer-related mRNAs were co-expressed with UCA1 and were involved in the regulation of the PI3K-Akt-mTOR signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated lncRNA-UCA1 contributes to the progression of gastric cancer through regulation of the PI3K-Akt-mTOR signaling pathway

Liang

Sui

et al. 2017

Toxicology Letters

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PI3K/Akt/mTOR Intracellular Pathway and Breast Cancer: Factors, Mechanism and Regulation

Abstract: Structure and regulation/deregulation of mTOR provides a greater insight into the action mechanism. Also, through this review, one could easily scan first and second generation inhibitors for PI3K/Akt/mTOR pathway besides targeted therapies for breast cancer and the precise role of mTOR.

Cited by 109 publications

References 0 publications

MicroRNA-92a-3p enhances functional recovery and suppresses apoptosis after spinal cord injury via targeting phosphatase and tensin homolog

MicroRNA-92a-3p enhances functional recovery and suppresses apoptosis after spinal cord injury via targeting phosphatase and tensin homolog

Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer

Dysregulated lncRNA-UCA1 contributes to the progression of gastric cancer through regulation of the PI3K-Akt-mTOR signaling pathway

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