Chemoresistance of colorectal cancer to 5-fluorouracil is associated with silencing of the BNIP3 gene through aberrant methylation

He, Jia; Li, Pei; Jiang, Heng; Yang, Weiwen; Chen, Jianfang; Liang, Houjie

doi:10.7150/jca.18171

Cited by 54 publications

(45 citation statements)

References 32 publications

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“…We can also hypothesize that the level of BNIP3 protein modifies the response to some kind of cellular stress and a decrease in the BNIP3 pro-apoptotic protein level in our LHON cell model, could negatively affect apoptosis induction, what in turn can lead to cell survival as in the case of BNIP3-negative cancer cells (He et al, 2017;Li et al, 2017). Our analyses of lymphoblasts with the 11778G>A mutation treated with different concentrations of testosterone could support this hypothesis.…”

Section: Discussionsupporting

confidence: 58%

“…Decreased expression of BNIP3 in some cases of cancers was found to be caused by epigenetic modification, hypermethylation, of the BNIP3 promoter (Okami et al, 2004;Lazarini et al, 2012;Li et al, 2017). Treatment of BNIP3-negative pancreatic and colorectal cancer cell lines with a DNA methylation inhibitor restored BNIP3 expression and increased chemosensitivity and cell death in those cell lines (He et al, 2017;Li et al, 2017). In our studies the methylation profile was not checked and the cause of the lower level of BNIP3 in LHON cybrids requires further investigation.…”

Section: Discussionmentioning

confidence: 63%

“…In our study we found that BNIP3, a protein which was previously widely investigated in cancer pathogenesis, was significantly decreased in LHON cybrids compared to control cells. This proapoptotic protein was previously reported to be downregulated in pancreatic adenocarcinoma (Okami et al, 2004), myelodysplastic syndromes (Lazarini et al, 2012), acute myeloid leukemia (Lazarini et al, 2012), triple negative breast cancer (Koop et al, 2009) and colorectal cancer (He et al, 2017). Tumors which showed loss of expression of BNIP3 were found to be more prone to metastases (Koop et al, 2009).…”

Section: Discussionmentioning

confidence: 95%

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Analysis of BNIP3 and BNIP3L/Nix expression in cybrid cell lines harboring two LHON-associated mutations.

et al. 2019

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Mitochondria are key players in cell death through the activation of the intrinsic apoptosis pathway. BNIP3 and BNIP3L/Nix are outer mitochondrial membrane bifunctional proteins which because of containing both BH3 and LIR domains play a role in cellular response to stress by regulation of apoptosis and selective autophagy. Leber’s Hereditary Optic Neuropathy (LHON) is the most common mitochondrial disease in adults, characterized by painless loss of vision caused by atrophy of the optic nerve. The disease in over 90% of cases is caused by one of three mutations in the mitochondrial genome: 11778G>A, 3460G>A or 14484T>C. The pathogenic processes leading to optic nerve degeneration are largely unknown, however, the most common explanation is that mtDNA mutations increase the apoptosis level in this tissue. Here we present the results of analysis of BNIP3 and BNIP3L/Nix proteins in cells harboring a combination of the 11778G>A and the 3460G>A LHON mutations. Experiments performed on cybrids revealed that BNIP3 protein level is decreased in LHON cells compared to controls. CCCP treatment resulted in apoptosis induction only in control cells. Moreover, we also noticed reduced level of autophagy in LHON cybrids. The presented results suggest that in cells carrying LHON mutations expression of proteins involved in regulation of apoptosis and autophagy is decreased what in turn may disturb cell death pathways in those cells and affect cellular response to stress.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 95%

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Analysis of BNIP3 and BNIP3L/Nix expression in cybrid cell lines harboring two LHON-associated mutations.

et al. 2019

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“…Bcl-2 interacting protein 3 (BNIP3) is another hypoxia-regulated protein belonging to the BH3-only Bcl-2 family that has proven to be involved in apoptosis, necrosis, autophagy, and mitophagy under hypoxia or ischemia [10,11]. BNIP3, which may be activated by HIF-1α due to its HREs-containing promoter, is expressed in hypoxic tumoral areas, contributing to hypoxia-induced cell death [12].…”

Section: Introductionmentioning

confidence: 99%

Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells

Méndez-Blanco

Fondevila

Fernández-Palanca

et al. 2019

Cancers

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Despite sorafenib effectiveness against advanced hepatocarcinoma (HCC), long-term exposure to antiangiogenic drugs leads to hypoxic microenvironment, a key contributor to chemoresistance acquisition. We aimed to study the role of hypoxia in the development of sorafenib resistance in a human HCC in vitro model employing the HCC line HepG2 and two variants with acquired sorafenib resistance, HepG2S1 and HepG2S3, and CoCl2 as hypoximimetic. Resistant cells exhibited a faster proliferative rate and hypoxia adaptive mechanisms, linked to the increased protein levels and nuclear translocation of hypoxia-inducible factors (HIFs). HIF-1α and HIF-2α overexpression was detected even under normoxia through a deregulation of its degradation mechanisms. Proapoptotic markers expression and subG1 population decreased significantly in HepG2S1 and HepG2S3, suggesting evasion of sorafenib-mediated cell death. HIF-1α and HIF-2α knockdown diminished resistant cells viability, relating HIFs overexpression with its prosurvival ability. Additionally, epigenetic silencing of Bcl-2 interacting protein 3 (BNIP3) was observed in sorafenib resistant cells under hypoxia. Demethylation of BNIP3 promoter, but not histone acetylation, restored BNIP3 expression, driving resistant cells’ death. Altogether, our results highlight the involvement of HIFs overexpression and BNIP3 methylation-dependent knockdown in the development of sorafenib resistance in HCC. Targeting both prosurvival mechanisms could overcome chemoresistance and improve future therapeutic approaches.

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“…Despite an enormous amount of effort spent in the development of therapies to treat CRC, the 5-year survival rate has increased slowly in the USA, from 60% during the 1980s to 66% during 2005 to 2011 (4). To a large extent, this discouraging observation is largely due to the fact that patients with CRC demonstrate resistance to both new and older anticancer drugs (3,5).…”

Section: Introductionmentioning

confidence: 99%

Integrin�β4 reduces DNA damage‑induced p53 activation in colorectal cancer

Zhao

Jing

et al. 2018

Oncol Rep

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Integrin contributes to the maintenance of cell adhesion. In turn, cell adhesion triggers certain integrin signaling cascades, and influences cell biological behavior. In the present study, we explored the role and mechanism of integrin β4 in the DNA damage response in colorectal cancer (CRC) using a three‑dimensional (3D) cell culture model. Under 3D culture condition, dispersed CRC cells automatically formed multicellular spheroids, which consisted of layers of cells with cell junctions commonly distributed. The expression level of integrin β4 in HCT116 3D cultures was slightly higher compared with two‑dimensional (2D) cultures, while the expression level in LoVo 3D cultures was similar to or slightly lower than that in 2D cultures. Knockdown of integrin β4 by lentiviral delivery of shRNA did not markedly change the architectural formation of 3D cultures under an inverted microscope or transmission electron microscope. Platinum increased p53 and p‑p53 (ser15) in a time‑dependent manner in 3D cultures. Knockdown of integrin β4 increased sensitivity to cisplatin (CDDP) in 3D cultures. Under 3D culture condition, knockdown of integrin β4 did not detectably change the basal p53 protein level but increased p53 and p‑p53 (ser15) protein accumulation induced by platinum. Integrin β4 knockdown did not detectably change p53 protein level in HCT116 2D cultures with or without CDDP treatment. Knockdown of wild‑type p53 decreased sensitivity to platinum in 3D cultures. Since it has been proven that platinum damages DNA to kill cells and p53 plays a key role in the DNA damage response, our results indicated that integrin β4 reduced DNA damage‑induced p53 activation to decrease chemosensitivity in CRC. This may be due to integrin β4 activation in 3D cultures.

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Chemoresistance of colorectal cancer to 5-fluorouracil is associated with silencing of the BNIP3 gene through aberrant methylation

Cited by 54 publications

References 32 publications

Analysis of BNIP3 and BNIP3L/Nix expression in cybrid cell lines harboring two LHON-associated mutations.

Analysis of BNIP3 and BNIP3L/Nix expression in cybrid cell lines harboring two LHON-associated mutations.

Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells

Integrin�β4 reduces DNA damage‑induced p53 activation in colorectal cancer

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