The specific role of pRb in p16<sup>INK4A</sup>-mediated arrest of normal and malignant human breast cells

Bazarov, Alexey V.; Lee, Won Jae; Bazarov, Irina; Bosire, Moses; Hines, William C.; Stankovich, Basha; Chicas, Agustin; Lowe, Scott W.; Yaswen, Paul

doi:10.4161/cc.11.5.19492

Cited by 21 publications

(14 citation statements)

References 26 publications

(24 reference statements)

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“…25 Between the cell cycle entry kinases, CDK4 and CDK6, CDK4 exhibits high affinity to p16 INK4a . 26,27 Contrary to this, we observed lack of strong interaction between CDK4 and p16 INK4a . However, the aberrant activation of CDK4/6 causes inappropriate pRb phosphorylation and thus proliferative robustness.…”

Section: Discussioncontrasting

confidence: 99%

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Compromising the constitutive p16^INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

Kanugovi

Joseph

Siripini

et al. 2019

J of Cellular Biochemistry

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The Hsp90 chaperone has become the attractive pharmacological target to inhibit tumor cell proliferation. However, tumor cells can evolve with mechanisms to overcome Hsp90 inhibition. Using human neuroblastoma, we have investigated one such limitation. Here, we demonstrate that neuroblastoma cells overcome the interference of tumor suppressor p16INK4a in cell proliferation, which is due to its latent interaction with CDK4 and CDK6. Cells also displayed impedance to the pharmacological inhibition of cancer chaperone Hsp90 inhibition with respect to induced cytotoxicity. However, the p16INK4a knockdown has triggered the activation of cyclin‐CDK6 axis and enhanced the cell proliferation. These cells are eventually sensitized to Hsp90 inhibition by activating the DNA damage response mediated through p53‐p21WAF‐1 axis and G1 cell cycle exit. While both CDK4 and CDK6 have exhibited low affinity to p16INK4a, CDK6 has exhibited high affinity to Hsp90. Destabilizing the CDK6 interaction with Hsp90 has prolonged G2/M cell cycle arrest fostering to premature cellular senescence. The senescence driven cells exhibited compromised metastatic potential both in vitro as well as in mice xenografts. Our study unravels that cancer cells can be adapted to the constitutive expression of tumor suppressors to overcome therapeutic interventions. Our findings display potential implication of Hsp90 inhibitors to overcome such adaptations.

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Section: Discussioncontrasting

confidence: 99%

“…Cell cycle regulation is mediated by the cross‐talk between cyclins and CDKs, where CDKs in association with D‐type cyclins expedites the cell cycle . Between the cell cycle entry kinases, CDK4 and CDK6, CDK4 exhibits high affinity to p16 INK4a . Contrary to this, we observed lack of strong interaction between CDK4 and p16 INK4a .…”

Section: Discussioncontrasting

confidence: 75%

Compromising the constitutive p16^INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

Kanugovi

Joseph

Siripini

et al. 2019

J of Cellular Biochemistry

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“…Senescence does not occur simultaneously during culture expansion and some cells may already have entered a senescent state, whereas others are still able to proliferate (Wagner 2010). All of the above-mentioned mechanisms ultimately result in DNA damage that triggers activation of common pathways such as TP53/CDKN1A and CDKN2A/RB1 (Seluanov et al 2001;Shay and Roninson 2004;Bazarov et al 2012;Sperka et al 2012). Pluripotent cells express telomerase and maintain telomere integrity over time, which may prevent replicative senescence (Marion et al 2009b).…”

mentioning

confidence: 99%

Pluripotent stem cells escape from senescence-associated DNA methylation changes

et al. 2012

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Pluripotent stem cells evade replicative senescence, whereas other primary cells lose their proliferation and differentiation potential after a limited number of cell divisions, and this is accompanied by specific senescence-associated DNA methylation (SA-DNAm) changes. Here, we investigate SA-DNAm changes in mesenchymal stromal cells (MSC) upon longterm culture, irradiation-induced senescence, immortalization, and reprogramming into induced pluripotent stem cells (iPSC) using high-density HumanMethylation450 BeadChips. SA-DNAm changes are highly reproducible and they are enriched in intergenic and nonpromoter regions of developmental genes. Furthermore, SA-hypomethylation in particular appears to be associated with H3K9me3, H3K27me3, and Polycomb-group 2 target genes. We demonstrate that ionizing irradiation, although associated with a senescence phenotype, does not affect SA-DNAm. Furthermore, overexpression of the catalytic subunit of the human telomerase (TERT) or conditional immortalization with a doxycyclineinducible system (TERT and SV40-TAg) result in telomere extension, but do not prevent SA-DNAm. In contrast, we demonstrate that reprogramming into iPSC prevents almost the entire set of SA-DNAm changes. Our results indicate that long-term culture is associated with an epigenetically controlled process that stalls cells in a particular functional state, whereas irradiation-induced senescence and immortalization are not causally related to this process. Absence of SADNAm in pluripotent cells may play a central role for their escape from cellular senescence.

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“…Certain breast cancer cell lines show a striking inability to overcome palbociclib induced growth arrest, even when Rb expression is inhibited, 13 in accordance with our own recent findings that in some instances Rb family members p107 and p130 can mediate growth arrest in the absence of Rb. 24 Other cell lines easily overcome arrest, despite the presence of intact Rb. These differences in adaptability may be mechanistically linked with the relative abilities of specific cell lineages to undergo EMT.…”

Section: Resistance To Targeted Therapies Is Tied To Changes In Cell mentioning

confidence: 99%

Reinforcing targeted therapeutics with phenotypic stability factors

Yaswen

2014

Cell Cycle

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The specific role of pRb in p16^INK4A-mediated arrest of normal and malignant human breast cells

Cited by 21 publications

References 26 publications

Compromising the constitutive p16^INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

Compromising the constitutive p16^INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

Pluripotent stem cells escape from senescence-associated DNA methylation changes

Reinforcing targeted therapeutics with phenotypic stability factors

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The specific role of pRb in p16INK4A-mediated arrest of normal and malignant human breast cells

Cited by 21 publications

References 26 publications

Compromising the constitutive p16INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

Compromising the constitutive p16INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

Pluripotent stem cells escape from senescence-associated DNA methylation changes

Reinforcing targeted therapeutics with phenotypic stability factors

Contact Info

Product

Resources

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The specific role of pRb in p16^INK4A-mediated arrest of normal and malignant human breast cells

Compromising the constitutive p16^INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

Compromising the constitutive p16^INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence