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Despite improvements in treatment, lung cancer is still a major health problem worldwide. Among lung cancer subtypes, the most frequent is represented by adenocarcinoma (belonging to the Non-Small Cell Lung Cancer class) although the most challenging and harder to treat is represented by Small Cell Lung Cancer, that occurs at lower frequency but has the worst prognosis. For these reasons, the standard of care for these patients is represented by a combination of surgery, radiation therapy and chemotherapy. In this view, searching for novel biomarkers that might help both in diagnosis and therapy is mandatory. In the last 30 years it was demonstrated that different families of ion channels are overexpressed in both lung cancer cell lines and primary tumours. The altered ion channel profile may be advantageous for diagnostic and therapeutic purposes since most of them are localised on the plasma membrane thus their detection is quite easy, as well as their block with specific drugs and antibodies. This review focuses on ion channels (Potassium, Sodium, Calcium, Chloride, Anion and Nicotinic Acetylcholine receptors) in lung cancer (both Non-Small Cell Lung Cancer and Small Cell Lung Cancer) and recapitulate the up-to-date knowledge about their role and clinical relevance for a potential use in the clinical setting, for lung cancer diagnosis and therapy.

Increasing evidence indicates that ion channels and transporters cooperate in regulating different aspects of tumor pathophysiology. In cancer cells, H+/HCO3- transporters usually invert the transmembrane pH gradient typically observed in non-neoplastic cells, which is thought to contribute to cancer malignancy. To what extent the pH-regulating transporters are functionally linked to K+ channels, which are central regulators of cell membrane potential (Vm), is unclear. We thus investigated in colorectal cancer cells the implication of the pH-regulating transporters and KV11.1 (also known as hERG1) in the pH modifications stimulated by integrin-dependent cell adhesion. Colorectal cancer cell lines (HCT 116 and HT 29) were seeded onto β1 integrin-dependent substrates, collagen I and fibronectin. This led to a transient cytoplasmic alkalinization, which peaked at 90 min of incubation, lasted approximately 180 min, and was inhibited by antibodies blocking the β1 integrin. The effect was sensitive to amiloride (10 µM) and cariporide (5 µM), suggesting that it was mainly caused by the activity of the Na+/H+ antiporter NHE1. Blocking KV11.1 with E4031 shows that channel activity contributed to modulate the β1 integrin-dependent pHi increase. Interestingly, both NHE1 and KV11.1 modulated the colorectal cancer cell motility triggered by β1 integrin-dependent adhesion. Finally, the β1 integrin subunit, KV11.1 and NHE1 co-immunoprecipitated in colorectal cancer cells seeded onto Collagen I, suggesting the formation of a macromolecular complex following integrin-mediated adhesion. We conclude that the interaction between KV11.1, NHE1, and β1 integrin contributes to regulate colorectal cancer intracellular pH in relation to the tumor microenvironment, suggesting novel pharmacological targets to counteract pro-invasive and, hence, pro-metastatic behavior in colorectal cancer.

Despite improvements in early diagnosis and treatment, breast cancer is still a major health problem worldwide. Among breast cancer subtypes, the most challenging and harder to treat is represented by triple-negative molecular subtype. Due to its intrinsic features this subtype cannot be treated neither with hormonal therapy (since it does not express estrogen or progesterone receptors) nor with epidermal growth factor receptor 2 (HER2) inhibitors (as it does not express high levels of this protein). For these reasons, the standard of care for these patients is represented by a combination of surgery, radiation therapy and chemotherapy. In this scenario, searching for novel biomarkers that might help both in diagnosis and therapy is mandatory. In the last years, it was shown that different families of potassium channels are overexpressed in primary breast cancers. The altered ion channel expression may be useful for diagnostic and therapeutic purposes due to some peculiar characteristics of this class of molecules. Ion channels are defined as pore-forming transmembrane proteins regulating passive ion fluxes in the cells. Ion channels represent good potential markers since, being localized at the plasma membrane level, their detection and block with specific drugs and antibodies might be fast and tunable. This review focuses on triple-negative breast cancers and recapitulates the current knowledge about potassium channels' clinical relevance and their potential use in the clinical setting, for triple-negative breast cancer diagnosis and therapy.