Human biliverdin reductase regulates the molecular mechanism underlying cancer development

Zhang, Min; Wei, Xin; Yi, Zhi; Li, Yue; Liu, Ying; Zhang, Hongyue; Chen, He; Chen, Xinxin; Tan, Shujie; Zhu, Daling

doi:10.1002/jcb.26285

Cited by 8 publications

(7 citation statements)

References 29 publications

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“…Results collected in the current study further strengthen the role of IL-8 and Caspase-3 in VAT dysfunction, by providing a potential mechanism associated with BVR-A and leading to their elevation. Indeed, as previously reported, BVR-A silencing leads to a significant increase of Caspase-3 levels in different cell types [35] whereas biliverdin administration significantly decreased the LPS-mediated IL-8 gene expression and secretion [36] thus supporting a role for BVR-A in controlling the inflammatory response [37]. In particular, the role of IL-8 and Caspase-3 in VAT inflammation was highlighted by several studies.…”

Section: Discussionmentioning

confidence: 52%

Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity

Ceccarelli

Barchetta

Cimini

et al. 2020

IJMS

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Biliverdin reductase A (BVR-A) is an enzyme involved in the regulation of insulin signalling. Knockout (KO) mice for hepatic BVR-A, on a high-fat diet, develop more severe glucose impairment and hepato-steatosis than the wild type, whereas loss of adipocyte BVR-A is associated with increased visceral adipose tissue (VAT) inflammation and adipocyte size. However, BVR-A expression in human VAT has not been investigated. We evaluated BVR-A mRNA expression levels by real-time PCR in the intra-operative omental biopsy of 38 obese subjects and investigated the association with metabolic impairment, VAT dysfunction, and biopsy-proven non-alcoholic fatty liver disease (NAFLD). Individuals with lower VAT BVR-A mRNA levels had significantly greater VAT IL-8 and Caspase 3 expression than those with higher BVR-A. Lower VAT BVR-A mRNA levels were associated with an increased adipocytes’ size. An association between lower VAT BVR-A expression and higher plasma gamma-glutamyl transpeptidase was also observed. Reduced VAT BVR-A was associated with NAFLD with an odds ratio of 1.38 (95% confidence interval: 1.02–1.9; χ2 test) and with AUROC = 0.89 (p = 0.002, 95% CI = 0.76–1.0). In conclusion, reduced BVR-A expression in omental adipose tissue is associated with VAT dysfunction and NAFLD, suggesting a possible involvement of BVR-A in the regulation of VAT homeostasis in presence of obesity.

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Section: Discussionmentioning

confidence: 52%

Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity

Ceccarelli

Barchetta

Cimini

et al. 2020

IJMS

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“…Apart from being used as a novel biomarker for nasopharyngeal carcinoma [45], UCB has the potential to cause cell cycle arrest at G0/G1 and exert pro-oxidant effects at high concentrations [46]. Human biliverdin reductase, which chemically reduces biliverdin to bilirubin, was recently implicated as a regulator in cancer development and maybe useful in designing biomarkers for cancer patients [47]. A similar study reported that lower serum bilirubin levels occur in colorectal cancer patients with a 1µM decrease in serum bilirubin related to a 7% rise in CRC risk [48].…”

Section: Discussionmentioning

confidence: 99%

Bilirubin Attenuates ER Stress-Mediated Inflammation, Escalates Apoptosis and Reduces Proliferation in the LS174T Colonic Epithelial Cell Line

Gundamaraju¹,

Vemuri²,

Chong³

et al. 2019

Int. J. Med. Sci.

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Mildly elevated serum unconjugated bilirubin (UCB) concentrations are associated with protection against disease conditions underpinned by cellular and metabolic stress. To determine the potential therapeutic efficacy of UCB we tested it in an in vitro model of gut inflammation. Tunicamycin TUN (10 µg/mL) was used to induce endoplasmic reticular stress (ERS) affecting N-glycosylation in LS174T cells. Cultured cells were investigated with addition of UCB at doses 0.1, 1 and 10µM (resulting in bilirubin:albumin ratios of 0.325-0.003)against ER stress-mediated effects including inflammation, cell survival (determined by apoptosis) and proliferation. Gene expression of ER stress markers (Grp78, Perk, XBP1 and ATF6) were evaluated in addition to cytokine concentrations in media after six hours of treatment. We then verified the potential role of UCB in executing programmed cell death via PARP, Caspase3 and Annexin V assays and further explored cell proliferation using the Click-iT EdU assay. A dose of 10µM UCB most potently reduced tunicamycin-mediated effects on enhanced UPR markers, inflammatory cytokines and proliferation; however all the doses (i.e.0.1-10µM) reduced the expression of ER stress and inflammatory markers Grp78, NLRP3, IL1-b, XBP1, PERK and ATF6. Furthermore, media concentrations of pro-inflammatory cytokines IL-8, IL-4 and TNFα decreased and the anti-inflammatory cytokine IL-10 increased (P<0.05). A dose of 10µM UCB initiated intrinsic apoptosis via Caspase 3 and in addition reduced cellular proliferation. Collectively, these data indicate that co treatment with UCB resulted in reducing ER stress response to TUN in gastrointestinal epithelial cells, reduced the subsequent inflammatory response, induced cancer cell death and decreased cellular proliferation. These data suggest that mildly elevated circulating or enteric UCB might protect against gastrointestinal inflammatory disorders.

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“…Also, BLVRA, another important enzyme in the heme catabolic pathway, has been proposed as promoting carcinogenesis [ 18 ]. In fact, the increased expression of BLVRA has been demonstrated in patients with hepatocellular cancer [ 19 ], as well as in breast and lung cancer cell lines [ 20 ]. Nevertheless, in our in vitro studies on human pancreatic cancer cells, we did not observe any effects of chlorophylls on BLVRA expression.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has been proposed that BLVRA plays a role in the promotion of carcinogenesis [ 18 ]. In fact, increased BLVRA expression has been observed in patients with hepatocellular cancer [ 19 ] and in breast and lung cancer cell lines [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Chlorophyll‐Mediated Changes in the Redox Status of Pancreatic Cancer Cells Are Associated with Its Anticancer Effects

Vaňková

Markova

Jašprová

et al. 2018

Oxidative Medicine and Cellular Longevity

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Nutritional factors which exhibit antioxidant properties, such as those contained in green plants, may be protective against cancer. Chlorophyll and other tetrapyrrolic compounds which are structurally related to heme and bilirubin (a bile pigment with antioxidant activity) are among those molecules which are purportedly responsible for these effects. Therefore, the aim of our study was to assess both the antiproliferative and antioxidative effects of chlorophylls (chlorophyll a/b, chlorophyllin, and pheophytin a) in experimental pancreatic cancer. Chlorophylls have been shown to produce antiproliferative effects in pancreatic cancer cell lines (PaTu-8902, MiaPaCa-2, and BxPC-3) in a dose-dependent manner (10–125 μmol/L). Chlorophylls also have been observed to inhibit heme oxygenase (HMOX) mRNA expression and HMOX enzymatic activity, substantially affecting the redox environment of pancreatic cancer cells, including the production of mitochondrial/whole-cell reactive oxygen species, and alter the ratio of reduced-to-oxidized glutathione. Importantly, chlorophyll-mediated suppression of pancreatic cancer cell viability has been replicated in in vivo experiments, where the administration of chlorophyll a resulted in the significant reduction of pancreatic tumor size in xenotransplanted nude mice. In conclusion, this data suggests that chlorophyll-mediated changes on the redox status of pancreatic cancer cells might be responsible for their antiproliferative and anticancer effects and thus contribute to the decreased incidence of cancer among individuals who consume green vegetables.

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Human biliverdin reductase regulates the molecular mechanism underlying cancer development

Cited by 8 publications

References 29 publications

Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity

Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity

Bilirubin Attenuates ER Stress-Mediated Inflammation, Escalates Apoptosis and Reduces Proliferation in the LS174T Colonic Epithelial Cell Line

Chlorophyll‐Mediated Changes in the Redox Status of Pancreatic Cancer Cells Are Associated with Its Anticancer Effects

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