BKCa promotes growth and metastasis of prostate cancer through facilitating the coupling between αvβ3 integrin and FAK

Abstract

BKCa is a large conductance calcium activated potassium channel promoting prostate cancer cell proliferation, although the mechanism is not fully elucidated. In addition, whether BKCa is involved in metastasis of prostate cancer remains to be explored. Here, we report that BKCa is overexpressed in prostate cancer. BKCa expression positively correlates with Ki67 index and gleason score of prostate cancer. Upregulation of BKCa promoted proliferation, migration and invasion of prostate cancer cells. On the contrary, downregulation of BKCa inhibited growth and metastasis of prostate cancer cells both in vitro and in vivo. Moreover, the ion-conducting function of BKCa contributed moderately to prostate cancer proliferation and migration, although, this was not the primary mechanism. BKCa action was mainly mediated through forming a functional complex with αvβ3 integrin. The BKCa/αvβ3 integrin complex promoted FAK phosphorylation independent of the channel activity. Overexpression of BKCa enhanced its association with αvβ3 integrin and FAK which increased FAK phosphorylation. Conversely, disrupting the complex by downregulation of BKCa reduced FAK phosphorylation. Finally, blocking of αvβ3 integrin or p-FAK activity using LM609 or Y15 markedly abrogated BKCa-enhanced cell proliferation and migration. Taken together, these results suggest that targeting BKCa/αvβ3/FAK may inaugurate innovative approaches to inhibit prostate cancer growth and metastasis.

Induced Pluripotent Stem Cell–Derived Podocyte-Like Cells as Models for Assessing Mechanisms Underlying Heritable Disease Phenotype: Initial Studies Using Two Alport Syndrome Patient Lines Indicate Impaired Potassium Channel Activity

“…In other cell types, KCNMA1 activation can protect cardiomyoblast cells from hypoxia/reperfusion damage (Fretwell and Dickenson, 2011) and reduce shock-induced reductions in vascular reactivity (Hu et al, 2014). KCNMA1 channel activity can also facilitate prostate cancer cell growth possibly through an association with avb3 integrin and focal adhesion kinase (Du et al, 2016). Although the absence of potassium channel function may explain the elevated intracellular calcium in AS1 (and AS2) podocyte-like cells, the mechanism underlying this effect was not immediately clear.…”

THSD7A expression in human cancer

“…FAK is overexpressed in several tumor types and is believed to play a role in tumor progression and metastasis . Therefore, FAK is discussed as an effective cancer target in various tumors …”

“…[9][10][11][12] Therefore, FAK is discussed as an effective cancer target in various tumors. [13][14][15][16][17] To our knowledge, there are no data on the association between THSD7A and human cancer. The demonstrated association between a malignant tumor and the development of MN raised the question whether THSD7A had been involved in the tumor development.…”

Evidence of BKCa Channelopathy-Driven Breast Cancer Metastasis to Brain

“…Targeting metastatic breast cancer cells in brain is extremely difficult as brain provides a "safe haven" for cancer cells. Gene expression profiling has been used to predict metastatic gene-expression signature that is present in a subset of primary breast tumors [8]. However, a reliable profile has not yet been identified that specifically predicts brain metastases.…”

“…Activation of BK Ca channels was shown to be a novel molecular pathway involved in zoledronic acidinduced apoptosis of MDA-MB-231 cells in vitro [32]. Du et al [8] showed that BK Ca promotes growth and metastasis of prostate cancer through facilitating the coupling between αvβ3 integrin and FAK. BK Ca channels are shown to support cancer cell migration, invasion and tumorigenesis [11,17,18].…”