Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program

Leontieva, Olga V.; Demidenko, Zoya N.; Blagosklonny, Mikhail V.

doi:10.1073/pnas.1405723111

Cited by 137 publications

(135 citation statements)

References 54 publications

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“…The presence of an additional product of the INK4a/b locus, with higher capacity to induce cellcycle arrest, may confer an added protection to naked mole rat cells, contributing to cancer resistance of this species. It was recently shown that contact inhibition represses mTOR and thus suppresses the senescence program (44). Thus, it is tempting to speculate that ECI in naked mole rats mediated by the unusual structure of the INK4a/b locus may contribute to naked mole rat longevity, in addition to conferring cancer resistance.…”

Section: Discussionmentioning

confidence: 99%

INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform

Tian

Azpurua

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The naked mole rat (Heterocephalus glaber) is a long-lived and tumor-resistant rodent. Tumor resistance in the naked mole rat is mediated by the extracellular matrix component hyaluronan of very high molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of naked mole rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15 INK4b , p16 INK4a , and ARF (alternate reading frame). Although p15 INK4b has its own ORF, p16 INK4a and ARF share common second and third exons with alternative reading frames. Here, we show that, in the naked mole rat, the INK4a/b locus encodes an additional product that consists of p15 INK4b exon 1 joined to p16 INK4a exons 2 and 3. We have named this isoform pALT INK4a/b (for alternative splicing). We show that pALT INK4a/b is present in both cultured cells and naked mole rat tissues but is absent in human and mouse cells. Additionally, we demonstrate that pALT INK4a/b expression is induced during early contact inhibition and upon a variety of stresses such as UV, gamma irradiation-induced senescence, loss of substrate attachment, and expression of oncogenes. When overexpressed in naked mole rat or human cells, pALT INK4a/b has stronger ability to induce cell-cycle arrest than either p15 INK4b or p16 INK4a . We hypothesize that the presence of the fourth product, pALT INK4a/b of the INK4a/b locus in the naked mole rat, contributes to the increased resistance to tumorigenesis of this species.naked mole rat | INK4 | p16 | p15

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Section: Discussionmentioning

confidence: 99%

INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform

Tian

Azpurua

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…13,[19][20][21][26][27][28][29][30][31][32][33][34] Senescence is an irreversible, proliferationinhibiting response that occurs in 2 steps: 1) reversible cell cycle arrest followed by 2) futile growth-induced gerogenic conversion, or geroconversion. [35][36][37] Moreover, senescence is a major tumorsuppressive mechanism that acts as an early barrier to thwart cancer development. The presence of senescent cells in benign lesions, but not advanced malignant tumors, suggests that senescence barriers must be dismantled during oncogenic progression.…”

Section: Introductionmentioning

confidence: 99%

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

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“…When cell cycle is arrested, the growth signal (if it cannot reactivate cycling) drives senescence. It was shown that inhibition of mTOR precludes senescence (by inhibiting the so called geroconversion) and causes reversible quiescence [26][27][28][29] . These data are in accord with our previous observation that isolated breast cancer cells, residually left behind after surgery and Temsirolimus treatment in mice, are quiescent for a certain time and eventually re-grow, resulting in tumor recurrence [9].…”

Section: Discussionmentioning

confidence: 99%

Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

Segatto¹,

Massarut²,

Boyle³

et al. 2016

European Journal of Cancer

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Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program

Cited by 137 publications

References 54 publications

INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform

INK4 locus of the tumor-resistant rodent, the naked mole rat, expresses a functional p15/p16 hybrid isoform

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

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