Ion channel control of cell-cycle progression and proliferation
Potassium and other voltage-gated channels influence whether a cell divides, rests or dies. hERG1, also called Kv11.1, is a prominent example discussed in several reviews. Rao and colleagues report that inhibiting it reduces proliferation in cancer cell lines.4 Perez-Neut and colleagues report that activating it raised p21waf/cip protein in breast cancer cells.6 Other authors link membrane voltage to the phase of the cell cycle.7
- Earliest held
- 2012, Pillozzi S, Becchetti A
- Most discussed in
- hERG1/Kv11.1 activation stimulates…, 2016
- In the library
- 59 passages in 16 works
- Rewritten
- 2026-10-21
Expression in blood and tumours
Pillozzi and Becchetti (2012) reviewed hERG1 in haematopoietic cells. They report that in stimulated CD34+ cells Kv11.1 associates with β1 integrin, which is essential for proper bone marrow engraftment.1 They also describe a complex of hERG1, β1 integrin and CXCR4 that appeared on acute lymphoblastic leukaemia cells after coculture with mesenchymal stem cells.2 Urrego and colleagues (2014) reported that Kv11.1 expression is largely confined to neoplastic cells, in solid and haematological malignancies, when compared with neighbouring normal tissue.3 These reports tie the channel to adhesion and survival signalling as well as to division.
Blockade, arrest and death
Rao, Perez-Neut, Kaja and Gentile (2015) wrote that inhibition of Kv11.1 reduces proliferation of cancer cell lines and activates apoptosis.4 In the same review they describe the effect of voltage-gated channel blockers as either cell cycle arrest or apoptosis. Arrest is seen at G0/G1 or at G2/M, with accumulation of the tumour suppressors p27kip1 and p21CIP1.5 They also cite knockdown of Kv10.1 by siRNA, which reduced cell proliferation in several cancer cell lines. They cite shRNA against hERG1 as well. It reduced the growth of SH-SY5Y neuroblastoma cells, and in the same study it reduced the growth of SH-SY5Y tumours in nude mice.5
Activation and p21
Perez-Neut, Rao and Gentile (2016) recall earlier work in which the hERG1/Kv11.1 activator NS1643 was applied to breast cancer cells. It increased Ca2+ entry and raised p21waf/cip protein, giving a senescence-like phenotype. Non-transformed cells showed no effect.6 The 2016 paper reports that NS1643 stimulates p21waf/cip transcription through activation of CN.6 Blocking Kv11.1 reduces proliferation in cancer cell lines, while activating it in breast cancer cells gives a senescence-like phenotype.
Voltage and cycle phase
Abdul Kadir, Stacey and Barrett-Jolley (2018) state that a hyperpolarized membrane potential blocks quiescent cells in G1 from entering S phase, and so blocks DNA synthesis.7 They present the rest of the scheme as hypothesis. Voltage-gated Na+ or Ca2+ channels would open to depolarise cells for the G0/G1 to S transition. Kv11.1 opening in S phase would repolarise them. They add that a threshold resting potential may be needed to drive DNA synthesis.7 Desoyer and colleagues (2026) add a membrane mechanism: depolarisation rearranges charged phospholipids in the plasma membrane.8
In stimulated CD34+ cells, KV11.1 associates with β 1 integrin, which is essential for proper bone marrow engraftment of these HPCs
Pillozzi S, Becchetti A, 2012 · Ion channels in hematopoietic and mesenchymal stem cells · open at passage 9Coculture of ALL cells with MSCs induced on the lymphoblast plasma membrane the expression of a signaling complex formed by hERG1, the β1 integrin subunit, and CXCR4.
Pillozzi S, Becchetti A, 2012 · Ion channels in hematopoietic and mesenchymal stem cells · open at passage 22Various studies have demonstrated this expression to be largely confined to neoplastic cells both in solid and haematological malignancies
Urrego D, Tomczak AP, Zahed F, Stühmer W, Pardo LA, 2014 · Potassium channels in cell cycle and cell proliferation · open at passage 14Inhibition of Kv11.1 results in reduced proliferation of cancer cell lines and activation of an apoptotic event resulting in cell death
Rao VR, Perez-Neut M, Kaja S, Gentile S, 2015 · Voltage-gated ion channels in cancer cell proliferation · open at passage 8The cell cycle arrest is observed either at the G0/G1 phase or the G2/M phase through the accumulation of tumor suppressors p27kip1 and p21CIP1
Rao VR, Perez-Neut M, Kaja S, Gentile S, 2015 · Voltage-gated ion channels in cancer cell proliferation · open at passage 50caused an increase in Ca2+ entry [6] and increased p21waf/cip protein level that resulted in a senescence-like phenotype while no effect was observed in non-transformed cells
Perez-Neut M, Rao VR, Gentile S, 2016 · hERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer… · open at passage 6A hyperpolarized membrane potential inhibits mitosis as it blocks quiescent cells in the G1 phase of the cell cycle from entering the S phase
Abdul Kadir L, Stacey M, Barrett-Jolley R, 2018 · Emerging Roles of the Membrane Potential: Action Beyond the Action Potential · open at passage 19Depolarisation has been shown to rearrange charged phospholipids within the plasma membrane
Desoyer C, Šupe R, Ghorbanpour S, Goswami D, Khalaj M…, 2026 · Cancer: A bioelectric disease? · open at passage 41