SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A

Liu, Wenguang; Wu, Manwu; Du, Hechun; Shi, Xiaoliang; Zhang, Tao; Li, Jie

doi:10.3892/ol.2018.7989

Cited by 24 publications

(18 citation statements)

References 27 publications

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“…colorectal, breast, ovarian, hepatocellular, lung, and pancreatic tumors) and its downregulation is associated with poor prognosis 16 – 18 . Consistent with these results, loss of SIRT6 leads to tumor formation and maintenance 8 and ectopic expression of SIRT6 inhibits cancer stem cell proliferation 19 , 20 . In other tumors (i.e.…”

Section: Introductionsupporting

confidence: 69%

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Iachettini¹,

Trisciuoglio

Rotili

et al. 2018

Cell Death Dis

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Sirtuin 6 (SIRT6) is a member of the NAD+-dependent class III deacetylase sirtuin family, which plays a key role in cancer by controlling transcription, genome stability, telomere integrity, DNA repair, and autophagy. Here we analyzed the molecular and biological effects of UBCS039, the first synthetic SIRT6 activator. Our data demonstrated that UBCS039 induced a time-dependent activation of autophagy in several human tumor cell lines, as evaluated by increased content of the lipidated form of LC3B by western blot and of autophagosomal puncta by microscopy analysis of GFP-LC3. UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity since the catalytic mutant H133Y failed to activate autophagy. At the molecular level, SIRT6-mediated autophagy was triggered by an increase of ROS levels, which, in turn, resulted in the activation of the AMPK-ULK1-mTOR signaling pathway. Interestingly, antioxidants were able to completely counteract UBCS039-induced autophagy, suggesting that ROS burst had a key role in upstream events leading to autophagy commitment. Finally, sustained activation of SIRT6 resulted in autophagy-related cell death, a process that was markedly attenuated using either a pan caspases inhibitor (zVAD-fmk) or an autophagy inhibitor (CQ). Overall, our results identified UBCS039 as an efficient SIRT6 activator, thereby providing a proof of principle that modulation of the enzyme can influence therapeutic strategy by enhancing autophagy-dependent cell death.

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Section: Introductionsupporting

confidence: 69%

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Iachettini¹,

Trisciuoglio

Rotili

et al. 2018

Cell Death Dis

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“…Proteins were separated by SDS-PAGE and transferred onto a nitrocellulose membrane. The membranes were blocked with 5% non-fat dried milk for 1 h and incubated with rabbit monoclonal anti-iNOS (cat.no.136918, 1:1,000, Abcam; Lizano et al, 2017 ), rabbit monoclonal anti-Arg-1 (cat.no.93668, 1:1,000, Cell Signaling Technology; Mogami et al, 2017 ), rabbit monoclonal anti-p-NF-κB (cat.no.3033, 1:1,000, Cell Signaling Technology; Yan et al, 2017 ), rat monoclonal anti-MHC II (cat.no.139365, 1:1,000, Abcam; Mori et al, 2015 ) and rabbit monoclonal anti-β-actin (cat.no.4970, 1:1,000, Cell Signaling Technology; Liu et al, 2018 ) overnight at 4°C. After being washed with Tris-buffered saline with TWEEN 20 (TBST) buffer, the membranes were incubated with anti-rabbit (cat.…”

Section: Methodsmentioning

confidence: 99%

Partial Depletion of Peripheral M1 Macrophages Reverses Motor Deficits in MPTP-Treated Mouse by Suppressing Neuroinflammation and Dopaminergic Neurodegeneration

Yan

Zhang

Lin

et al. 2018

Front. Aging Neurosci.

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Background: Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Inflammatory cytokines in the peripheral immune system can induce neuroinflammation in central nervous system (CNS). Whether the peripheral immune system is involved in PD is unclear. The present study investigated the contribution of the peripheral immune system to the neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) model of PD.Methods: MPTP was intraperitoneally injected into mice to generate a PD model. Mice received clodronate liposomes every 3 days to deplete peripheral macrophages. The percentages of macrophages were measured by flow cytometry at 1, 3, and 7 days after MPTP injection. Neurobehavioral parameters, protein expression, inflammatory cytokines release, and microglia activation were measured by the open field test, western blotting, quantitative polymerase chain reaction (qPCR), and immunofluorescence staining, respectively at 7 days after MPTP injection.Results: Our study revealed that intraperitoneal injection of MPTP could increase peripheral M1 macrophages levels. It also can induce T cells infiltration and cytokine release. Depletion of M1 macrophages by clodronate liposomes suppressed these inflammatory effects and blunted the loss of TH+ nigral neurons and functional impairments caused by MPTP.Conclusion: Our results indicated the critical role of M1 macrophages in the pathogenesis of PD and proposed inhibition of M1 macrophages as a promising therapeutic approach for neurodegeneration.

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“…Cell division cycle 25A (CDC25A), a member of the CDC25 phosphatase family, can inhibit the phosphorylation of the cyclin-dependent kinase (CDK) subunit, activate cyclin-CDK complexes and accordingly regulate cell cycle progression [41]. Emerging evidence suggests that the expression of CDC25A is elevated in a number of human cancers and is often associated with high grade tumors and a poor prognosis [42].…”

Section: Discussionmentioning

confidence: 99%

B7-H3 promotes the cell cycle-mediated chemoresistance of colorectal cancer cells by regulating CDC25A

Wang

et al. 2020

J. Cancer

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Colorectal cancer (CRC) is one of the most common malignancies, and chemoresistance is one of the key obstacles in the clinical outcome. Here, we studied the function of B7-H3 in regulating cell cycle-mediated chemoresistance in CRC. The ability of B7-H3 in regulating chemoresistance was investigated via cell viability, clonogenicity, apoptosis and cycle analysis in vitro. Moreover, the role of B7-H3/CDC25A axis in regulating chemoresistance in vivo in the xenograft tumor models by intraperitoneal injection of oxaliplatin (L-OHP) and CDC25A inhibitors. The correlation between B7-H3 and CDC25A was examined in the CRC patients by immunohistochemistry (IHC) and pathological analyses. We found that B7-H3 could effectively enhance the resistance to a chemotherapeutic drug (oxaliplatin or 5-fluorouracil) via CDC25A. B7-H3 regulated the expression of CDC25A by the STAT3 signaling pathway in CRC cells. Furthermore, overexpression of B7-H3 enhanced chemoresistance by reducing the G2/M phase arrest in a CDC25A-dependent manner. Silencing CDC25A or treatment with CDC25A inhibitor could reverse the B7-H3-induced chemoresistance of cancer cells. Moreover, both B7-H3 and CDC25A were significantly upregulated in CRC samples compared with normal adjacent tissues and that the levels correlated with tumor stage. CDC25A was positively correlated with B7-H3 expression in this cohort. Taken together, our findings provide an alternative mechanism by which CRC cells can acquire chemoresistance via the B7-H3/CDC25A axis.

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SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A

Cited by 24 publications

References 27 publications

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells

Partial Depletion of Peripheral M1 Macrophages Reverses Motor Deficits in MPTP-Treated Mouse by Suppressing Neuroinflammation and Dopaminergic Neurodegeneration

B7-H3 promotes the cell cycle-mediated chemoresistance of colorectal cancer cells by regulating CDC25A

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