Sodium bicarbonate transporter NBCe1 regulates proliferation and viability of human prostate cancer cells LNCaP and PC3

Abstract

Studies on cultured cancer cells or cell lines have revealed multiple acid extrusion mechanisms and their involvement in cancer cell growth and progression. In the present study, the role of the sodium bicarbonate transporters (NBCs) in prostate cancer cell proliferation and viability was examined. qPCR revealed heterogeneous expression of five NBC isoforms in human prostate cancer cell lines LNCaP, PC3, 22RV1, C4-2, DU145, and the prostate cell line RWPE-1. In fluorescence pH measurement of LNCaP cells, which predominantly express NBCe1, Na + and HCO 3 --mediated acid extrusion was identified by bath ion replacement and sensitivity to the NBC inhibitor S0859. NBCe1 knockdown using siRNA oligonucleotides decreased the number of viable cells, and pharmacological inhibition with S0859 (50 µM) resulted in a similar decrease. NBCe1 knockdown and inhibition also increased cell death, but this effect was small and slow. In PC3 cells, which express all NBC isoforms, NBCe1 knockdown decreased viable cell number and increased cell death. The effects of NBCe1 knockdown were comparable to those by S0859, indicating that NBCe1 among NBCs primarily contributes to PC3 cell proliferation and viability. S0859 inhibition also decreased the formation of cell spheres in 3D cultures. Immunohistochemistry of human prostate cancer tissue microarrays revealed NBCe1 localization to the glandular epithelial cells in prostate tissue and robust expression in acinar and duct adenocarcinoma. In conclusion, our study demonstrates that NBCe1 regulates acid extrusion in prostate cancer cells and inhibiting or abolishing this transporter decreases cancer cell proliferation.

Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

“…Because we ruled out any difference in the proliferative rate, cell cycle and apoptosis of pancreatic cancer cells in vitro or an effect on tumor growth in immunocompromised mice, these data indicate that Slc4a4 targeting in cancer cells imposes a cell-extrinsic alteration of the TME that hinders tumor growth and metastasis through the immune system. This might appear in contradiction with in vitro evidence performed in breast, prostate and colorectal cancer cells where Slc4a4 silencing negatively affects cancer cell proliferation [16][17][18] . Unlike other tissues, normal pancreatic duct epithelial cells are exposed to a heterogenous and fluctuating gradient of pH (for example, alkaline in the apical side while acidic in the basolateral side), and, therefore, they might better adapt to pH modifications 50 .…”

“…Contrasting evidence has proven that the reduction of SLC4A4 expression can both prohibit and promote cancer cell proliferation and migratory traits in vitro or in immunodeficient contexts, largely depending on the tumor cell type [16][17][18][19][20] . Nevertheless, to date, there are no in vivo studies that have examined SLC4A4 as a modulator of tumor pH and antitumor immune responses in pancreatic cancer.…”

FERMT1 contributes to the progression of prostate cancer through the p53 pathway

“…It is widely recognized that LNCaP and C4-2 cells exhibit androgen receptor (AR) positivity, while DU145 and PC3 cells lack AR expression 29 . Previous studies have shown that LNCaP is an androgen-responsive cell line, whereas C4-2, PC3, and DU145 are androgen-independent cell lines 30,31 .…”

A review of renal tubular acidosis

“…1,211 As with primary dRTA, the mechanisms responsible for clinical sequelae of primary pRTA are directly related to the effects of metabolic acidosis and that of specific mutations in transporters. 71 NBCE1 is present in many tissues, 71,212 including the kidney, 213 brain, 214 eye, 215 liver, 216 pancreas, 217 intestine, 218,219 prostate, 220 epididymis, 221 and heart. 222 In the kidney, NBCE1 is responsible for HCO 3 − transport in the proximal tubules.…”