ZnCl2 sustains the adriamycin-induced cell death inhibited by high glucose

Garufi, Alessia; Trisciuoglio, Daniela; Cirone, Mara; D’Orazi, Gabriella

doi:10.1038/cddis.2016.178

Cited by 14 publications

(14 citation statements)

References 63 publications

(98 reference statements)

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“…Data from the literature reported that PP2A activation, upon increased glucose flux, induces carbohydrate response element binding protein (ChREBP) dephosphorylation and nuclear translocation to bind to the proximal HIF1A promoter, stimulating its transcription and HIF-1α stabilization even in normoxic condition [26, 52–54] (Figure 6). Although we did not assess in this study the levels of ChREBP, in support of that mechanism we previously found that HG increases HIF-1α expression with upregulation of genes target of HIF-1 activity (i.e., GLUT-1 and HK2 ) [25]. Therefore, as hypoxia and HIF-1 activity have been shown to induce HIPK2 proteasomal degradation through several ubiquitin ligases, including WSB1 and Siah2 [21, 22], we supposed that HIF-1, even in normoxic condition, could be the link between HG condition and HIPK2 degradation.…”

Section: Discussionmentioning

confidence: 86%

Hyperglycemia triggers HIPK2 protein degradation

Baldari¹,

Garufi

Granato

et al. 2016

Oncotarget

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Homeodomain interacting protein kinase-2 (HIPK2) is an evolutionary conserved kinase that modulates several key molecular pathways to restrain tumor growth and induce p53-depending apoptotic cell-death in response to anticancer therapies. HIPK2 silencing in cancer cells leads to chemoresistance and cancer progression, in part due to p53 inhibition. Recently, hyperglycemia has been shown to reduce p53 phosphorylation at serine 46 (Ser46), the target residue of HIPK2, thus impairing p53 apoptotic function. Here we asked whether hyperglycemia could, upstream of p53, target HIPK2. We focused on the effect of high glucose (HG) on HIPK2 protein stability and the underlying mechanisms. We found that HG reduced HIPK2 protein levels, therefore impairing HIPK2-induced p53 apoptotic activity. HG-triggered HIPK2 protein downregulation was rescued by both proteasome inhibitor MG132 and by protein phosphatase inhibitors Calyculin A (CL-A) and Okadaic Acid (OA). Looking for the phosphatase involved, we found that protein phosphatase 2A (PP2A) induced HIPK2 degradation, as evidenced by directly activating PP2A with FTY720 or by silencing PP2A with siRNA in HG condition. The effect of PP2A on HIPK2 protein degradation could be in part due to hypoxia-inducible factor-1 (HIF-1) activity which has been previously shown to induce HIPK2 proteasomal degradation through several ubiquitin ligases. Validation analysed performed with HIF-1α dominant negative or with silencing of Siah2 ubiquitin ligase clearly showed rescue of HG-induced HIPK2 degradation. These findings demonstrate how hyperglycemia, through a complex protein cascade, induced HIPK2 downregulation and consequently impaired p53 apoptotic activity, revealing a novel link between diabetes/obesity and tumor resistance to therapies.

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Section: Discussionmentioning

confidence: 86%

Hyperglycemia triggers HIPK2 protein degradation

Baldari¹,

Garufi

Granato

et al. 2016

Oncotarget

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“…Accumulation of senescent cells in aged tissues may be driven by several factors including an increased rate of formation of senescent cells, loss of senescence immunosurveillance, bystander effects caused by secretory phenotype on neighbouring cells and upregulation of intrinsic anti-apoptotic factors (van Deursen, 2014). Since Zn ions are important mediators of apoptotic pathways, and can both enhance or repress functional apoptosis (Garufi et al, 2016;McCabe et al, 1993;Perry et al, 1997;Truong-Tran et al, 2000;Zalewski et al, 1994), manipulating the exposure of cells to Zn may be an effective strategy to modulate cell senescence or to promote the death of senescent cells. In support of this idea, quercetin, a natural polyphenol and Zn ionophore (Dabbagh-Bazarbachi et al, 2014), induced selective death of senescent endothelial cells over proliferating cells (Zhu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Changes in Zn homeostasis during long term culture of primary endothelial cells and effects of Zn on endothelial cell senescence

Malavolta

Costarelli

Giacconi

et al. 2017

Experimental Gerontology

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Endothelial cell senescence and Zn nutritional status influence cardiovascular disease. The influence of Zn appears dichotomous, hence it is imperative to understand the relationship with cellular senescence to improve knowledge about the molecular and cellular basis of the disease. Here we aimed to determine: 1) the impact of chronic exposure to a moderately high dose of Zn on senescence of endothelial cells; 2) the changes in Zn homeostasis during the lifespan of primary cultured endothelial cells; and 3) the susceptibility of proliferating and senescent endothelial cells to cell death after short term exposure to increasing doses of Zn and of the Zn chelator TPEN. Chronic exposure to Zn accelerated senescence and untreated cells at later passages, where doubling time had increased, displayed relocation of labile Zn and altered expression of genes involved in the response to Zn toxicity, including SLC30A1, SLC39A6, SLC30A5, SLC30A10 and metallothioneins, indicating that senescent cells have altered zinc homeostasis. Most Zn-dependent genes that were expressed differently between early and late passages were correlated with changes in the expression of anti-apoptotic genes. Short-term treatment with a high dose of Zn leads to cell death, but only in the population of cells at both earlier and later passages that had already entered senescence. In contrast, Zn depletion led to death of cells at earlier but not later passages, which suggests that there are sub-populations of senescent cells that are resistant to Zn depletion. This resistant senescent cell population may accumulate under conditions of Zn deficiency and contribute to vascular pathology.

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“…Similarly, hyperglycemia has been shown to reduce cancer cell response to therapies, conferring resistance to drug‐induced cell death . Interestingly, we have shown that it is possible to target hypoxia and hyperglycemia to rescue both HIPK2 and p53 function, restoring tumor response to therapies, in vitro and in vivo (Figure a). Therefore, these data strongly support our hypothesis that a mutual interaction may exist between cancer cells that have lost HIPK2 function and fibroblasts activation in the TME.…”

Section: Discussionmentioning

confidence: 81%

HIPK2 role in the tumor–host interaction: Impact on fibroblasts transdifferentiation CAF‐like

et al. 2019

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The dialogue between cancer cells and the surrounding fibroblasts, tumor‐associated macrophages (TAM), and immune cells can create a tumor microenvironment (TME) able to promote tumor progression and metastasis and induce resistance to anticancer therapies. Cancer cells, by producing growth factors and cytokines, can recruit and activate fibroblasts in the TME inducing their transdifferention in cancer‐associated fibroblasts (CAFs). Then, CAFs, in a reciprocal cross‐talk with cancer cells, sustain cancer growth and survival and support malignancy and tumor resistance to therapies. Therefore, the identification of the molecular mechanisms regulating the interplay between cancer cells and fibroblasts can offer an intriguing opportunity for novel diagnostic and therapeutic anticancer purpose. HIPK2 is a multifunctional tumor suppressor protein that modulates cancer cell growth and apoptosis in response to anticancer drugs and negatively regulates pathways involved in tumor progression and chemoresistance. HIPK2 protein downregulation is induced by hypoxia and hyperglycemia and HIPK2 knockdown favors tumor progression and resistance to therapy other than a pseudohypoxic, inflammatory, and angiogenic cancer phenotype. Therefore, we hypothesized that HIPK2 modulation in cancer cells could contribute to modify the tumor–host interaction. In support of our hypothesis, here we provide evidence that culturing human fibroblasts (hFB) with conditioned media derived from cancer cells undergoing HIPK2 knockdown (CMsiHIPK2) triggered their transdifferentiation CAF‐like, compared to hFB cultured with CM‐derived from HIPK2‐carrying control cancer cells. CAF transdifferentiation was identified by expression of several markers including α‐smooth muscle actin (α‐SMA) and collagen I and correlated with autophagy–mediated caveolin‐1 degradation. Although the molecular mechanisms dictating CAF‐transdifferentiation need to be elucidated, these results open the way to further study the role of HIPK2 in TME remodeling for prognostic and therapeutic purpose.

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ZnCl2 sustains the adriamycin-induced cell death inhibited by high glucose

Cited by 14 publications

References 63 publications

Hyperglycemia triggers HIPK2 protein degradation

Hyperglycemia triggers HIPK2 protein degradation

Changes in Zn homeostasis during long term culture of primary endothelial cells and effects of Zn on endothelial cell senescence

HIPK2 role in the tumor–host interaction: Impact on fibroblasts transdifferentiation CAF‐like

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