Clinical significance of P-class pumps in cancer

Abstract

P-class pumps are specific ion transporters involved in maintaining intracellular/extracellular ion homeostasis, gene transcription, and cell proliferation and migration in all eukaryotic cells. The present review aimed to evaluate the role of P-type pumps [Na⁺/K⁺ ATPase (NKA), H⁺/K⁺ ATPase (HKA) and Ca2⁺-ATPase] in cancer cells across three fronts, namely structure, function and genetic expression. It has been shown that administration of specific P-class pumps inhibitors can have different effects by: i) Altering pump function; ii) inhibiting cell proliferation; iii) inducing apoptosis; iv) modifying metabolic pathways; and v) induce sensitivity to chemotherapy and lead to antitumor effects. For example, the NKA β2 subunit can be downregulated by gemcitabine, resulting in increased apoptosis of cancer cells. The sarcoendoplasmic reticulum calcium ATPase can be inhibited by thapsigargin resulting in decreased prostate tumor volume, whereas the HKA α subunit can be affected by proton pump inhibitors in gastric cancer cell lines, inducing apoptosis. In conclusion, the present review highlighted the central role of P-class pumps and their possible use and role as anticancer cellular targets for novel therapeutic chemical agents.

Keywords: HKA; NKA; P-type ATPases; SERCA; cancer; pump subunits.

Figure 1.

Illustration of the structure and function of P-class pumps created by authors. (A) SERCA pump transports Ca²⁺ from the cytosol to the lumen. (B) The anti-transportation of 2H⁺ from the cytosol to the lumen and 2K⁺ from the lumen to the cytosol by HKA to regulate intracellular pH. (C) NKA is an anti-porter involved in moving 3 Na⁺ from the cytosol to the ECM for the charge of 2K⁺ being transported into the cytosol. All transportations take place in expense of ATP. ECM, extracellular matrix; SR, sarcoendoplasmic reticulum; SERCA, sarcoendoplasmic reticulum calcium ATPase; HKA, proton potassium ATPase; NKA, sodium potassium ATPase.

Figure 2.

Flowchart of selected papers.

Figure 3.

Expression levels of all eight NKA isoforms in 24 types of cancer (red) and their respective healthy tissues (blue). (A) ATP1A1, ATP1A2, ATP1A3 and ATP1A4. (B) ATP1B1, ATP1B2, ATP1B3 and ATP1B4. Data were collected and permitted for publication from the UALCAN resource. TPM, transcripts per million; TCGA, The Cancer Genome Atlas; NKA, Na⁺/K⁺ ATPase; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PAAD, pancreatic adenocarcinoma; PRAD, prostate adenocarcinoma; PCPG, pheochromocytoma and paragangliosarcoma; READ, rectal adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; THCA, thyroid carcinoma; THYM, thymoma; STAD, stomach adenocarcinoma; UCEC, uterine corpus endometrial carcinoma.

Figure 4.

Expression levels of SERCA in 24 cancer tissues compared with in healthy tissues. Data were collected and permitted for publication from the UALCAN resource. TPM, transcripts per million; TCGA, The Cancer Genome Atlas; SERCA, sarcoendoplasmic reticulum calcium ATPase; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PAAD, pancreatic adenocarcinoma; PRAD, prostate adenocarcinoma; PCPG, pheochromocytoma and paragangliosarcoma; READ, rectal adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; THCA, thyroid carcinoma; THYM, thymoma; STAD, stomach adenocarcinoma; UCEC, uterine corpus endometrial carcinoma.

Figure 5.

Expression levels of HKA in cancer compared with in healthy tissues across 24 types of cancer. Downregulation of HKA expression was markedly observed in esophageal carcinoma and stomach adenocarcinoma, and was less distinct in thyroid carcinoma. Overall expression in all other tissues appeared to be limited. Data were collected and permitted for publication from the UALCAN resource. TPM, transcripts per million; TCGA, The Cancer Genome Atlas; HKA, H⁺/K⁺ ATPase; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PAAD, pancreatic adenocarcinoma; PRAD, prostate adenocarcinoma; PCPG, pheochromocytoma and paragangliosarcoma; READ, rectal adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; THCA, thyroid carcinoma; THYM, thymoma; STAD, stomach adenocarcinoma; UCEC, uterine corpus endometrial carcinoma.