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Pivotal Role of Nitric Oxide in Chemo and Immuno Sensitization of Resistant Tumor Cells to Apoptosis

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Nitric Oxide and Cancer: Pathogenesis and Therapy

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Abstract

Nitric oxide (NO) has been the subject of many reports with respect to its role in cancer. These various reports were not consistent and often contradictory. On one hand, the levels of iNOS correlated with both the progression and carcinogenesis of certain tumors, whereas, on the other hand, the levels of iNOS or treatment with NO donors correlated with tumor regression. These contradictory findings were interpreted as due to the relative levels of generated NO, such as lower levels were pro-tumorigenic whereas high levels were anti-tumorigenic. Initial findings by us and others demonstrated that the induction of iNOS in resistant tumors or the treatment with NO donors resulted in the reversal of resistance and the tumor cells were chemo and immuno sensitized to cytotoxic stimuli. Consequently, we have extended our investigations to examine the biochemical and molecular underlying mechanisms responsible for NO-mediated chemo-immunosensitizing activities to apoptosis by cytotoxic agents. In our investigations, we have established, in several tumor cell lines, the highly dysregulated NF-κB/Snail/YY1/RKIP/PTEN/PI3K-AKT loop that regulates both drug/immune resistance and EMT/metastasis. This dysregulated loop was established by the demonstration that most tumor cells exhibit constitutively hyper-activated NF-κB and PI3K-AKT pathways that regulate cell viability, proliferation and anti-apoptotic pathways through a large number of downstream target gene products. Independent analyses revealed that the transcription factor Yin Yang 1 (YY1), downstream of NF-κB, was a repressor of the Fas and DR5 death receptors expression on many tumor cells and correlated with the tumor cells’ resistance to corresponding FasL and TRAIL death ligands, respectively, on the surface of cytotoxic lymphocytes. In addition, the overexpression of YY1 in tumor cells regulates positively the transcription repressor factor Snail that regulates both EMT and resistance. The recent findings demonstrated that the metastasis-suppressor gene product, Raf kinase inhibitor protein, RKIP, which is minimally expressed in many cancers, was involved in the reversal of drug/immune resistance when it is overexpressed. Overexpression of RKIP was also reported to inhibit both the Raf/MEK/ERK and NF-κB pathways and, thus, also inhibited YY1 and Snail downstream of NF-κB. Snail-mediated inhibition of RKIP and PTEN expressions resulted in maintaining the activation of the PI3K-AKT survival pathway and its crosstalk with the NF-κB pathway. Overexpression of RKIP resulted in the upregulation of PTEN and inhibition of PI3K-AKT and NF-κB and resulting in the downregulation of YY1 and Snail and sensitization to chemo-immune-mediated apoptosis.

Altogether, the above findings established the tightly dysregulated NF-κB/Snail/YY1/RKIP/PTEN/PI3K-AKT loop that regulates cell survival, cell proliferation, EMT/metastasis, and resistance to apoptotic stimuli by cytotoxic agents. This dysregulated loop was shown to be significantly altered by NO due to the findings that treatment with NO donors resulted in the S-nitrosylation of p50/p65 chains of NF-κB and S-nitrosylation of both YY1 and Snail and, thus, inhibiting their activities and resulting in the upregulation of RKIP and PTEN. These gene products, in turn, also inhibit NF-κB and PI3K, respectively, and potentiate the NO-mediated inhibitory activity. These effects result in the inhibition of cell viability, proliferation, EMT/metastasis, and sensitization to apoptosis by cytotoxic immune-chemo drugs. The findings in vitro of the sensitizing activities of NO donors were corroborated in part in vivo in mice bearing tumor xenografts.

In this chapter, we briefly review our findings and those of others of the anti-tumor chemo and immune sensitizing activities of NO donors through their interference, in part, of the highly dysregulated NF-κB/Snail/YY1/RKIP/PTEN/PI3K-AKT resistance and metastatic loop. We suggest that NO donors are a new class of therapeutic agents that can exert simultaneously multiple anti-tumor effects at the level of cell viability, cell proliferation, induction of EMT, and chemosensitizing activities. The development and clinical application of various NO donors in combination with various therapeutics in the treatment of resistant and metastatic tumors are highly warranted, provided they are subtoxic to normal tissues.

This paper has not been published nor is it under consideration to be published by any other journal.

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Abbreviations

CRC:

Colorectal cancer

CTL:

Cytotoxic T lymphocyte

DETANONOate:

Diethylenetriamine NONOate

DR4:

Death receptor 4

DR5:

Death receptor 5

EMT:

epithelial mesenchymal transition

FasL:

Fas ligand

iNOS:

Inducible nitric oxide synthase

NK:

Natural killer

NPI-0052:

Proteasome inhibitor

PDT:

Photodynamic therapy

Rituximab:

Chimeric anti-CD20 mAb

RKIP:

Raf kinase inhibitor protein

TRAIL:

TNF-related apoptosis-inducing ligand

YY1:

Yin-Yang 1

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Acknowledgments

The author acknowledges the various students, fellows and collaborators whose published reports were the subject of this review. They are Drs. S Baritaki, J Berenson, D Chatterjee, H Chen, H Garban, F Hongo, S Huerta-Yepez, H Liu, M Vega and K Yeung. The author also acknowledges the Jonsson Comprehensive Cancer Center at UCLA for its assistance. The following funding agencies that supported the various publications referred to in this review (1999-present, in alphabetical order) are listed below: the Bodossaki Foundation, the Boiron Research Foundation, the Department of Defense (DOD)/US Army, DAMD. 17-02-1-0023, the Department of Surgery at the University of Texas Southwestern (Shannon Funds), the Fogarty Fellowships (D43DW0001 13–14), the National Council of Science and Technology, NCI RO1CA107023-02 S1, NIH COBRE Grant Number P20RR17695, PRIN 2009 and FVG 2009 (Italy), Terry Fox Funds Grant HIM/2007/061, UC MEXUS, the UCLA AIDS Institute, the UCLA Gene Therapy Program, the UCLA SPORE in Prostate Cancer, Veterans’ Affairs VISN17 and the Vollmer Foundation. The author also acknowledges the assistance of Samantha Kaufhold, Daphne Liang, Kathy Nguyen and Anna Shvartsur for their assistance in the preparation of this manuscript.

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  1. Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, 90095, Los Angeles, CA, USA

    Benjamin Bonavida

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    Benjamin Bonavida

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Bonavida, B. (2015). Pivotal Role of Nitric Oxide in Chemo and Immuno Sensitization of Resistant Tumor Cells to Apoptosis. In: Bonavida, B. (eds) Nitric Oxide and Cancer: Pathogenesis and Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-13611-0_12

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