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

Soumyabrata Roy,Kai Lu,Mukti Kant Nayak,Avishek Bhuniya,Tithi Ghosh,Suman Kundu,Sarbari Ghosh,Rathindranath Baral,Partha Sarathi Dasgupta,Sujit Basu

doi:10.1074/jbc.m116.748970

Abstract

Lung 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. Furthermore, recurrence and metastasis of NSCLC correlate well with CD133+ve tumor cells, a small population of tumor cells that have been designated as cancer stem cells (CSC). We have demonstrated for the first time high expression of D2 dopamine (DA) receptors in CD133+ve adenocarcinoma NSCLC cells. Also, activation of D2 DA receptors in these cells significantly inhibited their proliferation, clonogenic ability, and invasiveness by suppressing extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT, as well as down-regulation of octamer-binding transcription factor 4 (Oct-4) expression and matrix metalloproteinase-9 (MMP-9) secretion by these cells. These results are of significance as D2 DA agonists that are already in clinical use for treatment of other diseases may be useful in combination with conventional chemotherapy and radiotherapy for better management of NSCLC patients by targeting both tumor cells and stem cell compartments in the tumor mass.

Highlights

Lung 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
We determined the expression of D2 DA receptors in the CD133-expressing tumor cell population in NSCLC cell lines A549 and NCI-H23
Tumor cells, we examined the effects of D2 DA receptor activation on the status of extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT phosphorylation in this population of tumor cells derived from NSCLC cell lines A549 and NCI-H23

Summary

Dopamine Receptors Regulate Cancer Stem Cells

The ALDH1 activity is mainly due to its ALDH1A1 (aldehyde dehydrogenase 1 family, member A1) isoform, an intracellular cytosolic isoenzyme that oxidizes intracellular aldehyde and controls several functions including drug resistance [30]. NSCLC cells expressing high ALDH1 activity show the characteristics of CSC such as increased proliferation, self-renewal, and resistance to chemotherapy in vitro, are highly tumorigenic in immunocompromised mice, and maintain heterogeneity like the parent tumors [27]. These ALDH1A1-expressing NSCLC cells are known for their clone formation ability, proliferation, growth, and migration in vitro [28]. Studies from our laboratory have further reported that D2 DA receptors can regulate different functions of normal progenitor and stem cells such as endothelial progenitor and mesenchymal stem cells [38, 39]. We selected adenocarcinoma of the lung, the most common histological type of NSCLC observed in patients, for our present study

Results

Discussion

Experimental Procedures