Functional cooperation between KCa3.1 and TRPC1 channels in human breast cancer: Role in cell proliferation and patient prognosis

Abstract

Intracellular Ca2+ levels are important regulators of cell cycle and proliferation. We, and others, have previously reported the role of KCa3.1 (KCNN4) channels in regulating the membrane potential and the Ca2+ entry in association with cell proliferation. However, the relevance of KC3.1 channels in cancer prognosis as well as the molecular mechanism of Ca2+ entry triggered by their activation remain undetermined. Here, we show that RNAi-mediated knockdown of KCa3.1 and/or TRPC1 leads to a significant decrease in cell proliferation due to cell cycle arrest in the G1 phase. These results are consistent with the observed upregulation of both channels in synchronized cells at the end of G1 phase. Additionally, knockdown of TRPC1 suppressed the Ca2+ entry induced by 1-EBIO-mediated KCa3.1 activation, suggesting a functional cooperation between TRPC1 and KCa3.1 in the regulation of Ca2+ entry, possibly within lipid raft microdomains where these two channels seem to co-localize. We also show significant correlations between KCa3.1 mRNA expression and poor patient prognosis and unfavorable clinical breast cancer parameters by mining large datasets in the public domain. Together, these results highlight the importance of KCa3.1 in regulating the proliferative mechanisms in breast cancer cells as well as in providing a promising novel target in prognosis and therapy.

The potassium channel KCa3.1 promotes cell proliferation by activating SKP2 and metastasis through the EMT pathway in hepatocellular carcinoma

“…KCa3.1 expression is often functionally linked to abnormal cell behaviors in multiple tumors, such as proliferation, apoptosis, and migration . Our results demonstrated that knockdown of KCa3.1 suppressed the proliferation, migration, invasion, and induced cell cycle arrest of HCC cells.…”

“…How could KCa3.1 expression influence the progression of tumors? Early reports have mainly focused on the intracellular calcium alterations induced by KCa3.1, which might explain the cellular biological behaviors resulting from KCa3.1 manipulation . Epigenetic dysregulation of KCa3.1 occurs in lung cancer and is associated with a worse prognosis of lung cancer patients .…”

“…KCa3.1 plays an important role not only in regulating cell volume but also in maintaining intracellular calcium homeostasis . The expression of KCa3.1 has been found to be correlated with malignancy in a variety of human cancers, such as glioblastoma, lung cancer, breast cancer, colorectal cancer, and kidney cancer . In addition, pharmacological blockade or gene silencing of KCa3.1 can inhibit proliferation, migration, and invasiveness in pancreatic cancer, endometrial carcinoma, and breast cancer …”

Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies?

“…Among the K ϩ channel types whose overexpression has been most implicated in proliferation of various cancer cells are voltage-gated K v 10.1 (EAG1, human gene KCNH1) (374) and K v 11.1 (HERG1, human gene KCNH2) (16,241,282), background K 2P 2.1 (TREK1, human gene KCNK2), K 2P 9.1 (TASK3, gene KCNK9) and K 2P 10.1 (TREK2, gene KCNK10) (386,398,512,534,561), Ca 2ϩ -dependent K Ca 1.1 (BK, Slo or MaxiK, gene KCNMA1) (42,162,347,363), and K Ca 3.1 (IK, gene KCNN4) (142,274), although the involvement of some other members from these groups was documented as well (reviewed in Refs. 226,385,496)…”

NONHSAT076754 aids ultrasonography in predicting lymph node metastasis and promotes migration and invasion of papillary thyroid cancer cells

“…It was reported in previous studies that specific lncRNAs might be potent prognostic and predictive biomarkers [28, 29]. LncRNAs do have some advantages as clinical biomarkers.…”