Inhibition of SIRT1 combined with gemcitabine therapy for pancreatic carcinoma

Gong, Daozhi; Zhang, Jiamin; Min, Yu; Zhuang, Bo; Guo, Qingqu

doi:10.2147/cia.s45064

Cited by 13 publications

(9 citation statements)

References 27 publications

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“…Tumor xenografts were treated with vehicle, G-1 at 0.5 mg/kg/day alone and in combination with Sirtinol at 10 mg/kg/day. 32 , 33 , 34 These administrations were well tolerated as no change in body weight or in food and water consumption was observed together with no evidence of reduced motor function. No significant difference in the mean weights or histologic features of the major organs (liver, lung, spleen and kidney) was also detected after killing among vehicle and ligand-treated mice, thus indicating a lack of toxic effects.…”

Section: Resultsmentioning

confidence: 97%

SIRT1 is involved in oncogenic signaling mediated by GPER in breast cancer

et al. 2015

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A number of tumors exhibit an altered expression of sirtuins, including NAD+-dependent histone deacetylase silent information regulator 1 (SIRT1) that may act as a tumor suppressor or tumor promoter mainly depending on the tumor types. For instance, in breast cancer cells SIRT1 was shown to exert an essential role toward the oncogenic signaling mediated by the estrogen receptor-α (ERα). In accordance with these findings, the suppression of SIRT1 led to the inhibition of the transduction pathway triggered by ERα. As the regulation of SIRT1 has not been investigated in cancer cells lacking ER, in the present study we ascertained the expression and function of SIRT1 by estrogens in ER-negative breast cancer cells and cancer-associated fibroblasts obtained from breast cancer patients. Our results show that 17β-estradiol (E2) and the selective ligand of GPER, namely G-1, induce the expression of SIRT1 through GPER and the subsequent activation of the EGFR/ERK/c-fos/AP-1 transduction pathway. Moreover, we demonstrate that SIRT1 is involved in the pro-survival effects elicited by E2 through GPER, like the prevention of cell cycle arrest and cell death induced by the DNA damaging agent etoposide. Interestingly, the aforementioned actions of estrogens were abolished silencing GPER or SIRT1, as well as using the SIRT1 inhibitor Sirtinol. In addition, we provide evidence regarding the involvement of SIRT1 in tumor growth stimulated by GPER ligands in breast cancer cells and xenograft models. Altogether, our data suggest that SIRT1 may be included in the transduction network activated by estrogens through GPER toward the breast cancer progression.

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Section: Resultsmentioning

confidence: 97%

SIRT1 is involved in oncogenic signaling mediated by GPER in breast cancer

et al. 2015

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“…6D) were observed as UES in PharmacoDB, of which FOXJ1 underexpression is a marker of poor prognosis in gastric cancer [133], reduced expression of FOXG1 is correlated with worse prognosis in breast cancer [134], FOXJ3 is inhibited by miR-517a and associated with lung and colorectal cancer cell proliferation and invasion [135,136], and FOXH1 is overexpressed in breast cancer, and FOXH1 inhibition reduces proliferation in breast cancer cell lines [137]. Although not UES in PharmacoDB, inhibition of the HST1 homolog, SIRT1, by Tenovin-6 inhibits the growth of acute lymphoblastic leukemia cells and enhances cytarabine cytotoxicity [138], enhances gemcitabine efficacy in pancreatic cancer cell lines, and improves survival in a pancreatic cancer mouse model [139]. Thus, loss of this gene module that positively regulates DNA replication initiation appears to be robustly involved in oncogenesis and is also synthetic lethal with gemcitabine and cytarabine.…”

Section: Resultsmentioning

confidence: 99%

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

Santos

Icyuz

Pound

et al. 2019

Preprint

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10Knowledge about synthetic lethality can be applied to enhance the efficacy of 11 anti-cancer therapies in individual patients harboring genetic alterations in their cancer 12 that specifically render it vulnerable. We investigated the potential for high-resolution 13 phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, 14 comprehensive, and quantitative assessment of drug-gene interaction for gemcitabine 15 and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures 16 yet distinct anti-tumor efficacy. Human deoxycytidine kinase (dCK) was conditionally 17 expressed in the S. cerevisiae genomic library of knockout and knockdown (YKO/KD) 18 strains, to globally and quantitatively characterize differential drug-gene interaction for 19 gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, 20 histone modification, chromatin remodeling, and apoptosis-related processes influence 21 gemcitabine specifically, while drug-gene interaction specific to cytarabine was less 22 enriched in Gene Ontology. Processes having influence over both drugs were DNA 23 repair and integrity checkpoints and vesicle transport and fusion. Non-GO-enriched 24 genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics 25 data were integrated to identify yeast-human homologs with correlated differential gene 26 2 expression and drug-efficacy, thus providing a unique resource to predict whether 27 differential gene expression observed in cancer genetic profiles are causal in tumor-28 specific responses to cytotoxic agents. 29 30 Keywords: 31 yeast phenomics, gene-drug interaction, genetic buffering, quantitative high 32 throughput cell array phenotyping (Q-HTCP), cell proliferation parameters (CPPs), 33 gemcitabine, cytarabine, recursive expectation-maximization clustering (REMc), 34 pharmacogenomics 35 36 Introduction: 37Genomics has enabled targeted therapy aimed at cancer driver genes and 38 oncogenic addiction [1], yet traditional cytotoxic chemotherapeutic agents remain among 39 the most widely used and efficacious anti-cancer therapies [2]. Changes in the genetic 40 network underlying cancer can produce vulnerabilities to cytotoxic chemotherapy that 41 further influence the therapeutic window and provide additional insight into their 42 mechanisms of action [3,4]. A potential advantage of so-called synthetic lethality-based 43 treatment strategies is that they could have efficacy against passenger gene mutation or 44 compensatory gene expression, while classic targeted therapies are directed primarily at 45 driver genes ( Fig. 1A). Quantitative high throughput cell array phenotyping of the yeast 46 knockout and knockdown libraries provides a phenomic means for systems level, high- 47resolution modeling of gene interaction [5][6][7][8][9], which is applied here to predict cancer-48 relevant drug-gene interaction through integration with cancer pharmacogenomics 49 resources ( Fig. 1B). 50Nucleoside analogs include a diverse group of co...

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“…However, SIRT1 inhibition in vivo was found to promote pancreatic cancer xenograft tumor growth [ 52 ]. In addition, SIRT1 has been shown to facilitate pancreatic cancer chemoresistance, while application of a combination therapy consisting of a SIRT1 inhibitor and gemcitabine has been shown to have enhanced efficacy for pancreatic cancer [ 53 , 54 ]. Here, we found that SIRT1 was highly expressed in pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 99%

SYT8 promotes pancreatic cancer progression via the TNNI2/ERRα/SIRT1 signaling pathway

Liang

Shi

et al. 2021

Cell Death Discov.

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Pancreatic cancer is a highly lethal malignancy due to failures of early detection and high metastasis in patients. While certain genetic mutations in tumors are associated with severity, the molecular mechanisms responsible for cancer progression are still poorly understood. Synaptotagmin-8 (SYT8) is a membrane protein that regulates hormone secretion and neurotransmission, and its expression is positively regulated by the promoter of the insulin gene in pancreatic islet cells. In this study, we identified a previously unknown role of SYT8 in altering tumor characteristics in pancreatic cancer. SYT8 levels were upregulated in patient tumors and contributed towards increased cell proliferation, migration, and invasion in vitro and in vivo. Increased SYT8 expression also promoted tumor metastasis in an in vivo tumor metastasis model. Furthermore, we showed that SYT8-mediated increase in tumorigenicity was regulated by SIRT1, a protein deacetylase previously known to alter cell metabolism in pancreatic lesions. SIRT1 expression was altered by orphan nuclear receptor ERRα and troponin-1 (TNNI2), resulting in cell proliferation and migration in an SYT8-dependent manner. Together, we identified SYT8 to be a central regulator of tumor progression involving signaling via the SIRT1, ERRα, and TNNI2 axis. This knowledge may provide the basis for the development of therapeutic strategies to restrict tumor metastasis in pancreatic cancer.

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Inhibition of SIRT1 combined with gemcitabine therapy for pancreatic carcinoma

Cited by 13 publications

References 27 publications

SIRT1 is involved in oncogenic signaling mediated by GPER in breast cancer

SIRT1 is involved in oncogenic signaling mediated by GPER in breast cancer

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

SYT8 promotes pancreatic cancer progression via the TNNI2/ERRα/SIRT1 signaling pathway

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