Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy induction

Ito, Masaaki; Yurube, Takashi; Kakutani, Kenichiro; Maeno, Kazuo; Takada, Toru; Terashima, Yoshiki; Kakiuchi, Yuji; Takeoka, Yoshiki; Miyazaki, Shingo; Kuroda, R.; Nishida, Kotaro

doi:10.1016/j.joca.2017.08.019

Cited by 87 publications

(122 citation statements)

References 53 publications

(51 reference statements)

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“…Western blotting demonstrated that mTORC1‐inhibiting rapamycin, temsirolimus, and everolimus successfully decreased mTOR and downstream p70/S6K phosphorylation but increased upstream Akt phosphorylation; however, curcumin did not affect phosphorylation. These mTORC1 inhibition‐induced changes in mTOR and related feedback signaling molecules were consistent with the mTORC1/RAPTOR RNAi results (Figure B) …”

Section: Pharmacological Mtor Signaling Modulation In Human Disc Cellssupporting

confidence: 87%

“…Then, mTORC1 inhibition‐mediated relief of this negative feedback loop activates IRS1, PI3K, Akt, and ERK in some cell types . This feedback system has been found in a variety of cancers and also non‐malignant intervertebral disc cells (Figure A) …”

Section: Rnai‐mediated Mtor Signaling Modulation In Human Disc Cellsmentioning

confidence: 85%

“…The objective of our second study was to elucidate the involvement and roles played by mTOR signaling in human disc NP cells (Figure A) …”

Section: Rnai‐mediated Mtor Signaling Modulation In Human Disc Cellsmentioning

confidence: 99%

“…Although the RNAi‐mediated modulation of mTOR signaling identified protective effects for mTORC1/RAPTOR suppression in human disc NP cells, pharmacological modulation is favorable compared with gene‐silencing therapy in clinical practice due to safety issues. Rapamycin, an mTORC1 inhibitor, extends mammalian lifespan and plays protective roles in chondrocytes .…”

Section: Pharmacological Mtor Signaling Modulation In Human Disc Cellsmentioning

confidence: 99%

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Autophagy and mTOR signaling during intervertebral disc aging and degeneration

et al. 2020

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Degenerative disc disease is a highly prevalent, global health problem that represents the primary cause of back pain and is associated with neurological disorders, including radiculopathy, myelopathy, and paralysis, resulting in worker disability and socioeconomic burdens. The intervertebral disc is the largest avascular organ in the body, and degeneration is suspected to be linked to nutritional deficiencies. Autophagy, the process through which cells self‐digest and recycle damaged components, is an important cell survival mechanism under stress conditions, especially nutrient deprivation. Autophagy is negatively controlled by the mammalian target of rapamycin (mTOR) signaling pathway. mTOR is a serine/threonine kinase that detects nutrient availability to trigger the activation of cell growth and protein synthesis pathways. Thus, resident disc cells may utilize autophagy and mTOR signaling to cope with harsh low‐nutrient conditions, such as low glucose, low oxygen, and low pH. We performed rabbit and human disc cell and tissue studies to elucidate the involvement and roles played by autophagy and mTOR signaling in the intervertebral disc. In vitro serum and nutrient deprivation studies resulted in decreased disc cell proliferation and metabolic activity and increased apoptosis and senescence, in addition to increased autophagy. The selective RNA interference‐mediated and pharmacological inhibition of mTOR complex 1 (mTORC1) was protective against inflammation‐induced disc cellular apoptosis, senescence, and extracellular matrix catabolism, through the induction of autophagy and the activation of the Akt‐signaling network. Although temsirolimus, a rapamycin derivative with improved water solubility, was the most effective mTORC1 inhibitor tested, dual mTOR inhibitors, capable of blocking multiple mTOR complexes, did not rescue disc cells. In vivo, high levels of mTOR‐signaling molecule expression and phosphorylation were observed in human intermediately degenerated discs and decreased with age. A mechanistic understanding of autophagy and mTOR signaling can provide a basis for the development of biological therapies to treat degenerative disc disease.

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Section: Pharmacological Mtor Signaling Modulation In Human Disc Cellssupporting

confidence: 87%

Section: Rnai‐mediated Mtor Signaling Modulation In Human Disc Cellsmentioning

confidence: 85%

“…The objective of our second study was to elucidate the involvement and roles played by mTOR signaling in human disc NP cells (Figure A) …”

Section: Rnai‐mediated Mtor Signaling Modulation In Human Disc Cellsmentioning

confidence: 99%

Section: Pharmacological Mtor Signaling Modulation In Human Disc Cellsmentioning

confidence: 99%

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Autophagy and mTOR signaling during intervertebral disc aging and degeneration

et al. 2020

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“…Autophagy is also regarded as an important cell survival mechanism, which can sustain metabolism and prevent the accumulation of damaged toxic proteins and organelles under stress. Ito et al demonstrated that resident disc cells utilize autophagy to cope with harsh, low-nutrient environments [49]. Miyazaki et al showed that SIRT1, as a potent treatment agent for human degenerative IVD disease, can protect against nutrient deprivation-induced mitochondrial apoptosis through autophagy induction in human NP cells [50].…”

Section: Discussionmentioning

confidence: 99%

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

et al. 2018

Cell Physiol Biochem

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Background/Aims: Intervertebral disc degeneration (IDD) is a pathological process that is the primary cause of low back pain and is potentially mediated by compromised stress defense. Sestrins (Sesn) promote cell survival under stress conditions and regulate AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling. Here, we investigated the expression of Sesn in normal and degraded nucleus pulposus (NP) cells and its potential roles during IDD pathogenesis. Methods: Sesn expression in normal and degraded NP cells was determined by quantitative polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. Sesn function was investigated by using Sesn knockdown and overexpression techniques with analysis of extracellular matrix (ECM), cell apoptosis, autophagy, AMPK, and mTOR activation. Results: In human cultured NP cells, Sesn expression was significantly decreased in degraded NP cells at both the RNA and protein levels. The expression of Sesn1, 2, and 3 increased after stimulation by 2-deoxyglucose (2-DG), an endoplasmic reticulum stress inducer. 2-DG could also increase cell apoptosis, promote extracellular matrix (ECM) degradation, and positively regulate autophagy in NP cells. Sesn knockdown by small interfering RNA increased NP cell apoptosis and ECM degradation under basal culture conditions and in the presence of 2DG. Conversely, Sesn overexpression mediated by plasmid transfection repressed IDD by enhancing autophagy, which was associated with changes in mTOR but not AMPK activation. Conclusions: Sesn expression is suppressed in degraded NP cells. In addition, Sesn inhibits stress-induced cell apoptosis and ECM degradation by enhancing autophagy, which is modulated though mTOR activity. Suppression of Sesn might therefore represent an important cellular dysfunction mechanism in the process of IDD.

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Does mTORC1 inhibit autophagy at dual stages?

Santhaseela

Jayavelu

2020

BioEssays

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Extensive studies have attributed the lysosomal localization of the mechanistic target of rapamycin complex 1 (mTORC1) during its activation. However, the exact biological significance of this lysosomal localization of mTORC1 remains ill‐defined. Interestingly, findings have shown that localization of the lysosome itself is altered under conditions influencing mTORC1 activity. In this perspective, we hypothesize that the localization of mTORC1 and lysosome could be interconnected in a way that manifests regulation of autophagy that is already under progression at the time of mTORC1 activation. This provides a new possibility for autophagy regulation whose complete mechanistic insights remain to be determined.

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Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy induction

Abstract: Selective interference of mTORC1/RAPTOR protects against inflammation-induced apoptosis, senescence, and matrix catabolism possibly through Akt and autophagy induction in human disc cells.

Cited by 87 publications

References 53 publications

Autophagy and mTOR signaling during intervertebral disc aging and degeneration

Autophagy and mTOR signaling during intervertebral disc aging and degeneration

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

Does mTORC1 inhibit autophagy at dual stages?

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