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Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumor cells
Olivia Crociani1, Leonardo Guasti, Manuela Balzi
1Department of Experimental Pathology and Oncology, University of Firenze, Viale G. B. Morgagni 50, 50134 Firenze, Italy.
Abstract:
The role of K(+) channel activity during cell cycle progression has become a research topic of considerable interest. Blocking of K(+) channels inhibits the proliferation of many cell types, although the mechanism of this inhibition is unclear. There is speculation that K(+) channels differentially regulate the electrical potential of the plasma membrane (V(m)) during proliferation. We have demonstrated that in tumor cells the value of V(m) is clamped to rather depolarized values by K(+) channels belonging to the HERG family. We report here that tumor cell lines preferentially express the herg1 gene and a truncated, N-deleted form that corresponds to herg1b. This alternative transcript is also expressed in human primary acute myeloid leukemias. Both HERG1 and HERG1B proteins are expressed on the plasma membrane of tumor cells and can form heterotetramers. The expression of HERG protein isoforms is strongly cell cycle-dependent, accounting for variations in HERG currents along the mitotic cycle. Moreover, the blocking of HERG channels dramatically impairs cell growth of HERG-bearing tumor cells. These results suggest that modulated expression of different K(+) channels is the molecular basis of a novel mechanism regulating neoplastic cell proliferation.
Insights
Potassium (K+) channels, particularly HERG family members, are crucial for tumor cell proliferation by regulating membrane potential. Blocking these channels inhibits cancer cell growth, suggesting a novel therapeutic target.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Potassium (K+) channel activity is increasingly recognized for its role in cell cycle progression.
- Inhibition of K+ channels has been observed to impede the proliferation of various cell types, though the underlying mechanisms remain elusive.
- Research suggests K+ channels may differentially regulate plasma membrane electrical potential (V(m)) during cell proliferation.
Purpose of the Study:
- To investigate the role of HERG family K+ channels in tumor cell proliferation.
- To determine the expression patterns of HERG channel isoforms in tumor cells and their relation to the cell cycle.
- To elucidate the impact of HERG channel activity on neoplastic cell growth.
Main Methods:
- Analysis of gene expression for herg1 and herg1b transcripts in tumor cell lines and primary leukemias.
- Detection of HERG1 and HERG1B protein expression on the plasma membrane.
- Assessment of HERG protein isoform expression across different cell cycle phases.
- Pharmacological blockade of HERG channels to evaluate effects on tumor cell growth.
Main Results:
- Tumor cells preferentially express the herg1 gene and its N-deleted variant, herg1b.
- Both HERG1 and HERG1B proteins are expressed on the tumor cell plasma membrane and can form heterotetramers.
- HERG protein isoform expression is cell cycle-dependent, influencing HERG currents throughout the mitotic cycle.
- Blocking HERG channels significantly impairs the proliferation of HERG-expressing tumor cells.
Conclusions:
- Modulated expression of HERG K+ channel isoforms is a key regulator of neoplastic cell proliferation.
- HERG channels play a critical role in maintaining the depolarized membrane potential observed in tumor cells.
- Targeting HERG channels represents a potential novel therapeutic strategy for cancer treatment.