Plasma membrane SK2 channel activity regulates migration and chemosensitivity of high‐grade serous ovarian cancer cells

• Published in: Molecular oncology 2024-08, Vol.18 (8), p.1853-1865
• Main Authors: Romito, Olivier, Lemettre, Aude, Chantôme, Aurélie, Champion, Ophélie, Couty, Noémie, Ouldamer, Lobna, Hempel, Nadine, Trebak, Mohamed, Goupille, Caroline, Potier‐Cartereau, Marie
• Format: Article
• Language: English
• Subjects: Calcium channels; Calcium conductance; Calcium influx; Cancer; Cell adhesion & migration; Cell culture; Cell migration; Channel gating; Chemoresistance; chemosensitivity; Chemotherapy; Colorectal cancer; Drug resistance; Endoplasmic reticulum; Gene expression; high‐grade serous ovarian cancer; ION Channels; LPA; Lysophosphatidic acid; Melanoma; Membrane conductance; Ovarian Cancer; Paclitaxel; Plasma; Potassium; Potassium conductance; Prognosis; RNA; RNA-mediated interference; Short Report; siRNA; SK2 channel; Software; Survival analysis; Taxol; Tumor cell lines
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13631

No data are currently available on the functional role of small conductance Ca2+‐activated K+ channels (SKCa) in ovarian cancer. Here, we characterized the role of SK2 (KCa2.2) in ovarian cancer cell migration and chemosensitivity. Using the selective non‐cell‐permeant SK2 inhibitor Lei‐Dab7, we identified functional SK2 channels at the plasma membrane, regulating store‐operated Ca2+ entry (SOCE) in both cell lines tested (COV504 and OVCAR3). Silencing KCNN2 with short interfering RNA (siRNA), or blocking SK2 activity with Lei‐Dab7, decreased cell migration. The more robust effect of KCNN2 knockdown compared to Lei‐Dab7 treatment suggested the involvement of functional intracellular SK2 channels in both cell lines. In cells treated with lysophosphatidic acid (LPA), an ovarian cancer biomarker of progression, SK2 channels are a key player of LPA pro‐migratory activity but their role in SOCE is abolished. Concerning chemotherapy, SK2 inhibition increased chemoresistance to Taxol® and low KCNN2 mRNA expression was associated with the worst prognosis for progression‐free survival in patients with serous ovarian cancer. The dual roles of SK2 mean that SK2 activators could be used as an adjuvant chemotherapy to potentiate treatment efficacy and SK2 inhibitors could be administrated as monotherapy to limit cancer cell dissemination. Functional plasma membrane and intracellular SK2 channels participate in cell migration of serous ovarian cancer cells. Plasma membrane SK2 is a key player of cell migration induced by lysophosphatidic acid (LPA), an ovarian cancer biomarker of progression. Under LPA, the SK2 current increases, but the channel no longer contributes to the SOCE. Furthermore, the activity of plasma membrane SK2 channels promotes Taxol® sensitivity.