Activation of D2 Dopamine Receptors in CD133+ve Cancer Stem Cells in Non-small Cell Lung Carcinoma Inhibits Proliferation, Clonogenic Ability, and Invasiveness of These Cells

Abstract

Edited by Xiao-Fan WangLung carcinoma is the leading cause of cancer-related death worldwide, and among this cancer, non-small cell lung carcinoma (NSCLC) comprises the majority of cases. Globally, lung cancers are considered to be the leading causes of cancer-related deaths, and non-small cell lung carcinoma (NSCLC) 4 is the predominant type of lung cancer, occurring in 85% of the cases (1, 2). The prognosis of NSCLC is poor, and the survival rate is only 15% after 5 years because many of these patients ultimately do not respond to chemotherapy and radiotherapy due to the presence of CSC (3-5). The CSC have the unique ability to promote tumor growth, recurrence, metastasis, and resistance to treatment (6, 7).Moreover, CD133, a surface glycoprotein with a five-transmembrane domain, has been widely used as a surface marker to identify CSC in many human tumors including NSCLC (8 -12). Although CD133 is expressed in various human tissues, its glycosylated epitopes specific for stem cells may be discordant or sometimes absent, making it difficult to identify this cell population (13). There may be transcriptional or post-translational modifications (14), leading to some degree of alteration in its expression, or variation in its expression in different tumors may be due to the use of antibodies from different clones (12). However, despite these limitations, recent results from different laboratories have shown significant association of CD133 (epitope-1) expression in a population of tumor cells with CSC characteristics in the brain, prostate, liver, and lung (15-18).There are now several reports that have further strengthened the concept of CD133ϩve tumor cells as CSC in NSCLC as these tumor cells possess the characteristics of CSC (18 -20). In contrast to the CD133Ϫve tumor cells, CD133ϩve tumor cells are more tumorigenic and resistant to radiation and anticancer drugs (18 -20). These cells also have a greater ability to form anchorage-independent floating spheres, proliferation, and tumor mass than the CD133Ϫve NSCLC cells. The CD133ϩve cells like CSC demonstrate significantly increased stemness, adhesion, motility, and expression of drug efflux gene (21-23) than CD133Ϫve tumor cells. Importantly, the presence of CD133ϩve tumor cells correlates well with poor prognosis, decreased survival, and increased lymph node metastasis in NSCLC patients (24 -26).Furthermore, in addition to CD133, aldehyde dehydrogenase 1 (ALDH1) is also used as a CSC marker in NSCLC (12,(27)(28)(29)(30) 4 The abbreviations used are: NSCLC, non-small cell lung carcinoma; CSC, cancer stem cell(s); D 2 DA, D 2 dopamine (DA) receptors; ERK1/2, extracellular signal-regulated kinases 1/2; MMP-9, matrix metalloproteinase-9; MTT, 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide; PI, propidium iodide.

Curcumin Suppresses Lung Cancer Stem Cells via Inhibiting Wnt/β-catenin and Sonic Hedgehog Pathways

“…For example, CD133, CD44 and aldehyde dehydrogenase (ALDH) are widely used in the identification of lung CSCs. CD133-positive lung cells exhibit strong tumorigenic potential and drugresistant ability (Bertolini et al, 2009;Chen et al, 2008;Liu et al, 2013;Roy et al, 2016). Elevated expression level of CD44 enhances tumor initiation capability in lung cancer (Leung et al, 2010).…”

Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis

“…Dopamine receptors (DR) and dopamine have been revealed to exhibit various pleiotropic properties through dependent and independent pathways, and their modulation has enhanced the efficiency of anticancer drugs in preclinical cancer models (40,41). In particular, DRD2 agonists have recently been shown to suppress proliferation, angiogenesis, and invasion in several cancers and tumors (42)(43)(44). Such studies paired with epidemiologic data implicate a relationship between lower rates of cancer development in patients with Parkinson, intimating a possible link between DR agonists and cancer (45,46).…”

Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma

“…Recently, high expression of DA D 2 receptors was demonstrated in CD133 + non-small-cell lung cancer cells, the activation of which significantly inhibited the proliferation and invasiveness of these cells in vitro (65). In addition, it was hypothesized that the expression of DA D 1 en D 2 receptors in small-cell lung cancer inhibited immune cell responses without affecting tumor growth (66).…”