Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.

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16K prolactin induces NF-kappaB activation in pulmonary fibroblasts

Journal of Endocrinology ◽

10.1677/joe.0.175r013 ◽

2002 ◽

Vol 175 (3) ◽

pp. R13-R18 ◽

Cited By ~ 13

Author(s):

Y Macotela ◽

C Mendoza ◽

AM Corbacho ◽

G Cosio ◽

JP Eiserich ◽

...

Keyword(s):

Nitric Oxide ◽

Nuclear Translocation ◽

Signal Transduction Pathway ◽

Binding Activity ◽

Inos Expression ◽

Pulmonary Fibroblasts ◽

Amino Terminal ◽

Dna Binding Activity ◽

Nf Kappab ◽

Oxide Synthase

The amino-terminal 16 kDa fragment of prolactin (16K PRL) promotes the expression of the inducible isoform of nitric oxide synthase (iNOS) accompanied by the production of nitric oxide (NO) by rat pulmonary fibroblasts. The present study was designed to elucidate whether the mechanism by which 16K PRL promotes iNOS expression involves the activation of nuclear factor-kappa B (NF-kappaB), a key transcription factor for iNOS induction. 16K PRL stimulated DNA-binding activity of NF-kappaB in pulmonary fibroblasts as demonstrated by gel shift assays. Likewise, fluorescence immunocytochemistry showed that 16K PRL promotes nuclear translocation of the p65 subunit of NF-kappaB. Finally, treatment with 16K PRL induced the degradation of the NF-kappaB inhibitor kappaB-beta (IkappaB-beta), and such degradation was prevented by blocking IkappaB-beta phosphorylation. Altogether, these results show that 16K PRL activates NF-kappaB nuclear translocation via the phosphorylation and degradation of IkappaB-beta. These findings are consistent with NF-kappaB being part of the signal transduction pathway activated by 16K PRL to induce iNOS expression.

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Membrane-bound TNF mediates microtubule-targeting chemotherapeutics-induced cancer cytolysis via juxtacrine inter-cancer-cell death signaling

Cell Death and Differentiation ◽

10.1038/s41418-019-0441-3 ◽

2019 ◽

Vol 27 (5) ◽

pp. 1569-1587 ◽

Cited By ~ 2

Author(s):

Jing Zhang ◽

Yu Yang ◽

Shen’ao Zhou ◽

Xueyan He ◽

Xuan Cao ◽

...

Keyword(s):

Cell Death ◽

Tumor Cells ◽

Cancer Cell ◽

Tumor Regression ◽

Cell Types ◽

Tight Contact ◽

Cancer Cell Death ◽

Microtubule Targeting Agents ◽

Patient Responsiveness ◽

Smac Mimetics

Abstract Microtubule-targeting agents (MTAs) are a class of most widely used chemotherapeutics and their mechanism of action has long been assumed to be mitotic arrest of rapidly dividing tumor cells. In contrast to such notion, here we show—in many cancer cell types—MTAs function by triggering membrane TNF (memTNF)-mediated cancer-cell-to-cancer-cell killing, which differs greatly from other non-MTA cell-cycle-arresting agents. The killing is through programmed cell death (PCD), either in way of necroptosis when RIP3 kinase is expressed, or of apoptosis in its absence. Mechanistically, MTAs induce memTNF transcription via the JNK-cJun signaling pathway. With respect to chemotherapy regimens, our results establish that memTNF-mediated killing is significantly augmented by IAP antagonists (Smac mimetics) in a broad spectrum of cancer types, and with their effects most prominently manifested in patient-derived xenograft (PDX) models in which cell–cell contacts are highly reminiscent of human tumors. Therefore, our finding indicates that memTNF can serve as a marker for patient responsiveness, and Smac mimetics will be effective adjuvants for MTA chemotherapeutics. The present study reframes our fundamental biochemical understanding of how MTAs take advantage of the natural tight contact of tumor cells and utilize memTNF-mediated death signaling to induce the entire tumor regression.

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High glucose induced NF-κB DNA-binding activity in HAEC is maintained under low shear stress but inhibited under high shear stress: role of nitric oxide

Atherosclerosis ◽

10.1016/j.atherosclerosis.2003.08.023 ◽

2003 ◽

Vol 171 (2) ◽

pp. 225-234 ◽

Cited By ~ 17

Author(s):

S Mohan

Keyword(s):

Nitric Oxide ◽

Shear Stress ◽

High Glucose ◽

Binding Activity ◽

High Shear ◽

High Shear Stress ◽

Dna Binding Activity ◽

Low Shear Stress ◽

Low Shear

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Indomethacin induced inhibition of AP-1 DNA-binding activity inhibits resistance of H202-resistant tumor cells to the cytotoxicity of hyperthermia, H202, and cisplatin

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/s0360-3016(00)80373-9 ◽

2000 ◽

Vol 48 (3) ◽

pp. 285-286

Author(s):

J Locke ◽

I Zoberi ◽

D.R Spitz ◽

D Gius

Keyword(s):

Dna Binding ◽

Tumor Cells ◽

Binding Activity ◽

Dna Binding Activity

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Aloe emodin inhibits colon cancer cell migration/angiogenesis by downregulating MMP-2/9, RhoB and VEGF via reduced DNA binding activity of NF-κB

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2011.12.012 ◽

2012 ◽

Vol 45 (5) ◽

pp. 581-591 ◽

Cited By ~ 62

Author(s):

Priya Suboj ◽

Suboj Babykutty ◽

Deepak Roshan Valiyaparambil Gopi ◽

Rakesh S. Nair ◽

Priya Srinivas ◽

...

Keyword(s):

Colon Cancer ◽

Cell Migration ◽

Dna Binding ◽

Cancer Cell ◽

Binding Activity ◽

Colon Cancer Cell ◽

Cancer Cell Migration ◽

Dna Binding Activity ◽

Aloe Emodin

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Nitric oxide-induced reduction of lung cell and whole lung thioredoxin expression is regulated by NF-κB

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.4.l787 ◽

1999 ◽

Vol 277 (4) ◽

pp. L787-L793 ◽

Cited By ~ 5

Author(s):

Jianliang Zhang ◽

Leonard W. Velsor ◽

Jawaharlal M. Patel ◽

Edward M. Postlethwait ◽

Edward R. Block

Keyword(s):

Nitric Oxide ◽

Dna Binding ◽

Nuclear Factor Κb ◽

Binding Activity ◽

Nuclear Fraction ◽

Cytosol Fraction ◽

Intact Mouse ◽

Α Subunit ◽

Dna Binding Activity ◽

Mouse Lungs

We examined whether nitric oxide (NO)-induced inhibition of thioredoxin (Thx) expression is regulated by a mechanism mediated by a transcription factor, i.e., nuclear factor-κB (NF-κB), in cultured porcine pulmonary artery endothelial cells (PAEC) and in mouse lungs. Western blot analysis revealed that IκB-α content was reduced by 20 and 60% in PAEC exposed to 8.5 ppm NO for 2 and 24 h, respectively. NO exposure also caused significant reductions of cytosol fraction p65 and p52 content in PAEC. The nuclear fraction p65 and p52 contents were significantly reduced only in PAEC exposed to NO for 24 h. Exposure to NO resulted in a 50% reduction of p52 mRNA but not of the IκB-α subunit. DNA binding activity of the oligonucleotide encoding the NF-κB sequence in the Thxgene was significantly reduced in PAEC exposed to NO for 24 h. Exposure of mice to 10 ppm NO for 24 h resulted in a significant reduction of lung Thx and IκB-α mRNA and protein expression and in the oligonucleotide encoding Thx and NF-κB/DNA binding. These results 1) demonstrate that the effects of NO exposure on Thx expression in PAEC are comparable to those observed in intact lung and 2) suggest that reduced expression of the NF-κB subunit, leading to reduced NF-κB/DNA binding, is associated with the loss of Thx expression in PAEC and in intact mouse lungs.

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Retinoid-induced apoptosis and Sp1 cleavage occur independently of transcription and require caspase activation.

Molecular and Cellular Biology ◽

10.1128/mcb.17.11.6348 ◽

1997 ◽

Vol 17 (11) ◽

pp. 6348-6358 ◽

Cited By ~ 86

Author(s):

F J Piedrafita ◽

M Pfahl

Keyword(s):

T Cells ◽

Dna Binding ◽

Cancer Cell ◽

De Novo ◽

Binding Activity ◽

Dependent Manner ◽

Intact Cells ◽

Dna Binding Activity ◽

Induced Apoptosis

Vitamin A and its derivatives, the retinoids, are essential regulators of many important biological functions, including cell growth and differentiation, development, homeostasis, and carcinogenesis. Natural retinoids such as all-trans retinoic acid can induce cell differentiation and inhibit growth of certain cancer cells. We recently identified a novel class of synthetic retinoids with strong anti-cancer cell activities in vitro and in vivo which can induce apoptosis in several cancer cell lines. Using an electrophoretic mobility shift assay, we analyzed the DNA binding activity of several transcription factors in T cells treated with apoptotic retinoids. We found that the DNA binding activity of the general transcription factor Sp1 is lost in retinoid-treated T cells undergoing apoptosis. A truncated Sp1 protein is detected by immunoblot analysis, and cytosolic protein extracts prepared from apoptotic cells contain a protease activity which specifically cleaves purified Sp1 in vitro. This proteolysis of Sp1 can be inhibited by N-ethylmaleimide and iodoacetamide, indicating that a cysteine protease mediates cleavage of Sp1. Furthermore, inhibition of Sp1 cleavage by ZVAD-fmk and ZDEVD-fmk suggests that caspases are directly involved in this event. In fact, caspases 2 and 3 are activated in T cells after treatment with apoptotic retinoids. The peptide inhibitors also blocked retinoid-induced apoptosis, as well as processing of caspases and proteolysis of Sp1 and poly(ADP-ribose) polymerase in intact cells. Degradation of Sp1 occurs early during apoptosis and is therefore likely to have profound effects on the basal transcription status of the cell. Interestingly, retinoid-induced apoptosis does not require de novo mRNA and protein synthesis, suggesting that a novel mechanism of retinoid signaling is involved, triggering cell death in a transcriptional activation-independent, caspase-dependent manner.

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Nitric oxide (NO) directly inhibits OCT1 DNA binding activity in cultured vascular smooth muscle cells (VSMCs).

Clinical Pharmacology & Therapeutics ◽

10.1038/sj.clpt.1996.196 ◽

1996 ◽

Vol 59 (2) ◽

pp. 174-174

Author(s):

X-K. Liu ◽

D. R. Abernethy ◽

Y. Li ◽

O. Shahine ◽

N. S. Andrawis

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Dna Binding ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Binding Activity ◽

Dna Binding Activity

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Age alters cerebrovascular inflammation and effects of estrogen

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01057.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. H2333-H2340 ◽

Cited By ~ 29

Author(s):

Lorraine Sunday ◽

Christa Osuna ◽

Diana N. Krause ◽

Sue P. Duckles

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Dna Binding ◽

Inducible Nitric Oxide Synthase ◽

Binding Activity ◽

Cerebral Vessels ◽

Cerebral Blood Vessels ◽

Dna Binding Activity ◽

Oxide Synthase ◽

Inducible Nitric Oxide

In young adult females, estrogen treatment suppresses the cerebrovascular inflammatory response; this is mediated in part via NF-κB, a key regulator of inflammatory genes. To examine whether age modifies effects of estrogen on vascular inflammation in the brain, female rats, 3 and 12 mo of age, were ovariectomized; half were treated with estrogen for 4 wk. Cerebral blood vessels were isolated from the animals at 4 and 13 mo of age. Inflammation was induced by LPS, either injected in vivo or incubated with isolated vessels ex vivo. Basal levels of cytoplasmic NF-κB were significantly higher in cerebral vessels of young rats, but the ratio of nuclear to cytoplasmic levels was greater in middle-aged animals. LPS exposure increased nuclear NF-κB DNA binding activity, protein levels of inducible nitric oxide synthase and cyclooxygenase-2, and production of nitric oxide and PGE2 in cerebral vessels. All effects of LPS were markedly greater in vessels from the older animals. Estrogen significantly inhibited the LPS-induced increase in NF-κB DNA binding activity in cerebral vessels from animals at both ages. In 4-mo-old rats, estrogen also significantly suppressed LPS induction of inducible nitric oxide synthase and cyclooxygenase-2 proteins, as well as production of nitric oxide and PGE2. In contrast, in 13-mo-old females, estrogen did not significantly affect these indexes of cerebrovascular inflammation. Thus the protective, anti-inflammatory effect of estrogen on cerebral blood vessels that is observed in young adults may be attenuated in aged animals, which exhibit a greater overall cerebrovascular response to inflammatory stimuli.

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