Nitric oxide is cytoprotective to breast cancer spheroids vulnerable to estrogen-induced apoptosis

Abstract

Estrogen-induced apoptosis has become a successful treatment for postmenopausal metastatic, estrogen receptor-positive breast cancer. Nitric oxide involvement in the response to this endocrine treatment and its influence upon estrogen receptor-positive breast cancer progression is still unclear.Nitric oxide impact on the MCF7 breast cancer line, before and after estrogen-induced apoptosis, was investigated in 3D culture systems using unique live-cell imaging methodologies.Spheroids were established from MCF7 cells vulnerable to estrogen-induced apoptosis, before and after exposure to estrogen.Spheroids derived from estrogen-treated cells exhibited extensive apoptosis levels with downregulation of estrogen receptor expression, low proliferation rate and reduced metabolic activity, unlike spheroids derived from non-treated cells. In addition to basic phenotypic differences, these two cell cluster types are diverse in their reactions to exogenous nitric oxide.A dual effect of nitric oxide was observed in the breast cancer phenotype sensitive to estrogen-induced apoptosis. Nitric oxide, at the nanomolar level, induced cell proliferation, high metabolic activity, downregulation of estrogen receptor and enhanced collective invasion, contributing to a more aggressive phenotype. Following hormone supplementation, breast cancer 3D clusters were rescued from estrogen-induced apoptosis by these low nitric oxide-donor concentrations, since nitric oxide attenuates cell death levels, upregulates survivin expression and increases metabolic activity.Higher nitric oxide concentrations (100nM) inhibited cell growth, metabolism and promoted apoptosis. These results suggest that nitric oxide, in nanomolar concentrations, may inhibit estrogen-induced apoptosis, playing a major role in hormonal therapy. Inhibiting nitric oxide activity may benefit breast cancer patients and ultimately reduce tumor recurrence.

Involvement of endothelial nitric oxide synthase gene variants in the aggressiveness of uterine cervical cancer

“…However, studies have showed that NO may also play an important role in cancer related pathophysiology such as modifying the expression of oncogene and tumor suppressor gene, tumor angiogenesis and metastasis [1]. NO has different actions in various human cancers such as head and neck cancer, breast cancer, gastric cancer, lung cancer and gynecologic cancers [1][2][3][4].…”

The long noncoding RNA sONE represses triple‐negative breast cancer aggressiveness through inducing the expression of miR‐34a, miR‐15a, miR‐16, and let‐7a

“…Several decades of literature highly supports the involvement NO as a pleiotropic onco-regulatory gasotransmitter in several types of cancers including BC (Shafran et al, 2017;Yarlagadda, Hassani, Foote, & Markowitz, 2017). Recently, eNOS-induced NO production has been highly implicated in determining the aggressiveness of TNBC tumors (Cranford et al, 2017;Trimmer et al, 2011;).…”

New 1,2,3-triazole/1,2,4-triazole hybrids linked to oxime moiety as nitric oxide donor selective COX-2, aromatase, B-RAF V600E and EGFR inhibitors celecoxib analogs: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis and molecular modeling study

“…Moreover, NO can prevent tumour cells from metastasising and assists macrophage to kill tumour cells 55 . Furthermore, evidences showed that low levels (nanomolar) of NO promote tumour cell proliferation, angiogenesis and metastasis, while higher concentrations sensitivity of tumours to chemotherapy and overcome drug resistance 56 . Therefore combination of high concentrations NO donors and cancer therapy increases its efficiency 57 .…”