Targeting the PI3-Kinase/Akt/mTOR Signaling Pathway

Burhan, Hassan; Akçakanat, Argun; Holder, Ashley M.; Meric‐Bernstam, Funda

doi:10.1016/j.soc.2013.06.008

Cited by 156 publications

(109 citation statements)

References 190 publications

(143 reference statements)

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“…Once PI3K is activated, its catalytic subunit activates AKT by phosphorylating AKT and successively activates mTOR by phosphorylating mTOR. The activation of mTOR leads to phosphorylation of p70S6K1, a mediator of protein translation and cell growth (27)(28)(29). It has also been demonstrated that Cyclin D1, a PI3K/AKT pathway downstream factor, is associated with abnormal proliferation, invasion, and thus prognosis of cancer (30).…”

Section: Discussionmentioning

confidence: 99%

Cantharidin suppresses cell growth and migration, and activates autophagy in human non-small cell lung cancer cells

Liu

et al. 2018

Oncol Lett

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Abstract. Cantharidin (CTD), a component of Mylabris (blister beetle), is a traditional Chinese medicine that exerts an anticancer effect in multiple types of cancer cells. The aim of the present study was to investigate whether CTD exhibited anti-metastatic and inhibitory cell proliferation effects against human non-small cell lung cancer (NSCLC) A549 cells, and the possible underlying mechanism by which this occurs. The results of the present study demonstrated that CTD arrested proliferation, suppressed invasion and migration and induced apoptosis in A549 cells in vitro. Alterations of apoptosis-associated protein levels, including B-cell lymphoma-2 (Bcl-2), Bcl-associated X (Bax) and active caspase-3, were detected. Furthermore, the present study demonstrated that CTD activated autophagy through downregulation of p62 expression and upregulation of microtubule-associated proteins 1A/1B light chain 3B and Beclin-1 expression. Additionally, western blot analysis identified that CTD inhibited the phosphatidylinositol 3-kinase (PI3K)/RAC serine/threonine protein kinase (Akt)/mechanistic target of rapamycin (mTOR) signaling pathway in NSCLC, demonstrating that the levels of phosphorylated (p-)Akt, p-mTOR, phosphorylated ribosomal p70S6 protein kinase (p-p70-S6K) and cyclin D1 were significantly decreased following treatment with CTD. In conclusion, the results of the present study indicated that CTD impeded cell growth and migration by inhibiting PI3K/Akt/mTOR signaling in NSCLC, and promoted autophagy and apoptosis. CTD exhibited anticancer activity against NSCLC in vitro, revealing it as a potential candidate for the treatment of NSCLC.

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Section: Discussionmentioning

confidence: 99%

Cantharidin suppresses cell growth and migration, and activates autophagy in human non-small cell lung cancer cells

Liu

et al. 2018

Oncol Lett

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“…mTOR, a key regulator of protein translation 28 , propagates the signaling from AKT activation and phosphorylates several downstream targets. Given the importance of PI3K/AKT/mTOR signaling in the development of human cancers, the inhibitory function of JNU-144 towards cell growth and proliferation may be attributed to its suppression of mTOR activation.…”

Section: Discussionmentioning

confidence: 99%

A new meroterpenoid functions as an anti-tumor agent in hepatoma cells by downregulating mTOR activation and inhibiting EMT

Wan

Zhang

et al. 2018

Sci Rep

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Liver cancer, also known as primary liver cancer, is cancer that starts in the liver. JNU-144, a new meroterpenoid purified from Lithospermum erythrorhizon, has exhibited promising anticancer activity; however, the molecular mechanisms of action of JNU-144 on malignant cells remain unclear. Our studies revealed that JNU-144 suppressed cell viability and proliferation in hepatoma cells by downregulating mTOR activation. Meanwhile, JNU-144 activated the intrinsic apoptosis pathway and subsequently triggered apoptotic cell death in SMMC-7721 cells. We also found that JNU-144 inhibited the epithelial–mesenchymal transition in both SMMC-7721 and HepG2 cells through reprogramming of epithelial–mesenchymal transition (EMT)-related gene expression or regulating protein instability. These findings indicate that JNU-144 exerts potent anticancer activity in hepatoma cells and may be developed as a potential therapeutic drug.

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“…Our findings corroborated those of the previous studies. 18,19,[25][26][27]31,33 Moreover, inflammatory reaction switched on by IR injury in organs with the generation of ROS and oxidative stress and immune response would, in turn, further contribute to organ dysfunction. 27 Intriguingly, the present study further revealed an association between an increased level of inflammatory and ROS/ oxidative stress parameters and enhancement of kidney injury score and the deterioration of renal function in IR animals.…”

Section: Discussionmentioning

confidence: 99%

Enhanced protection against renal ischemia–reperfusion injury with combined melatonin and exendin-4 in a rodent model

Chang

Hsu

Yang

et al. 2016

Exp Biol Med (Maywood)

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We tested the hypothesis that combined treatment with melatonin, an anti-oxidant, and exendin-4, an anti-inflammatory agent, was superior to either alone for protecting the kidney from ischemia-reperfusion (IR) injury. Male adult Sprague-Dawley rats (n¼40) were equally divided into group 1 (sham-operated control), group 2 (IR only, IR¼1h/72h), group 3 (IR-exendin-4, 10 mg/kg at 30 min, 24 h, 48 h after IR procedure), group 4 (IR-melatonin, i.p. 50 mg at 30 min, then 20 mg at 6 and 18 h after IR procedure), and group 5 (combined IR-exendin-4-melatonin). All animals were sacrificed by 72 h after IR/sham procedure. The results showed that the kidney injury score, plasma creatinine, and blood urea nitrogen (BUN) levels were highest in group 2 and lowest in group 1, significantly higher in groups 3 and 4 than those in group 5 and significantly higher in group 3 than those in group 4 (all p < 0.001). The protein expressions of inflammatory (toll-like receptor 4, inducible nitric oxide synthase, interleukin1b), apoptotic (mitochondrial Bax, cleaved caspase-3 and poly(ADP-ribose) polymerase, p53), podocyte integrity (E-cadherin, P-cadherin), and cell survival (phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin) biomarkers, as well the podocyte dysfunction biomarkers (Wnt1/Wnt4/b-catenin) displayed a pattern identical to that of creatinine level among the five groups (all p < 0.001). Microscopic findings demonstrated that podocyte dysfunction (Wnt1/Wnt4/b-catenin expression) and inflammatory (CD14 and F4/80-positively stained cells) biomarkers exhibited an identical pattern, whereas that of antioxidant (HO-1 þ , NQO-1 þ cells) biomarkers showed an opposite pattern compared to that of creatinine level among the five groups (all p < 0.001). Combined melatonin-exendin-4 therapy offered an additional benefit in protecting the kidney from acute IR injury.

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Targeting the PI3-Kinase/Akt/mTOR Signaling Pathway

Cited by 156 publications

References 190 publications

Cantharidin suppresses cell growth and migration, and activates autophagy in human non-small cell lung cancer cells

Cantharidin suppresses cell growth and migration, and activates autophagy in human non-small cell lung cancer cells

A new meroterpenoid functions as an anti-tumor agent in hepatoma cells by downregulating mTOR activation and inhibiting EMT

Enhanced protection against renal ischemia–reperfusion injury with combined melatonin and exendin-4 in a rodent model

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