Impact of intracellular ion channels on cancer development and progression

Abstract

Cancer research is nowadays focused on the identification of possible new targets in order to try to develop new drugs for curing untreatable tumors. Ion channels have emerged as “oncogenic” proteins, since they have an aberrant expression in cancers compared to normal tissues and contribute to several hallmarks of cancer, such as metabolic re-programming, limitless proliferative potential, apoptosis-resistance, stimulation of neo-angiogenesis as well as cell migration and invasiveness. In recent years, not only the plasma membrane but also intracellular channels and transporters have arisen as oncological targets and were proposed to be associated with tumorigenesis. Therefore, the research is currently focusing on understanding the possible role of intracellular ion channels in cancer development and progression on one hand and, on the other, on developing new possible drugs able to modulate the expression and/or activity of these channels. In a few cases, the efficacy of channel-targeting drugs in reducing tumors has already been demonstrated in vivo in preclinical mouse models.

Pharmacological modulation of mitochondrial ion channels

“…Interestingly, many of the K + channels found in the IMM (in addition to the PM and other membranes) are highly overexpressed in cancer cells/tissues. For example, the two‐pore leak channel K 2P 9.1(TASK‐3) is overexpressed five‐ to 100‐fold in 44% of breast tumours and is also highly expressed in lung, colon and ovarian cancers (Peruzzo et al ., ). Its overexpression promotes tumour formation and confers resistance to hypoxia in vitro , suggesting that its up‐regulation plays a pathologically important role in human breast cancer (Mu et al ., ).…”

“…MCU is overexpressed in several type of cancer cells (e.g. Davis et al ., ; Peruzzo et al ., ; Bustos et al ., ) and has been implicated in cancer‐related processes, in particular in the control of migration and metastasis (Hall et al ., ; Tang et al ., ; Tosatto et al ., ; Szabo and Leanza, ).…”

“…An important opportunity for intervention to modulate these processes is offered by mitochondrial ion channels (reviews on mitochondrial channels; Brini et al ., ; Citi et al ., ; Krabbendam et al ., ; Mammucari et al ., ; O'Rourke, ; Ponnalagu and Singh, ; Szabo and Zoratti, ; Szewczyk et al ., ). These channels are especially important, at least in the contexts of cancer (Figure ) (for reviews, see Leanza et al ., 2013a, 2014b; Madamba et al ., ; Peruzzo et al ., ; Mazure, ; Szabo and Leanza, ; Shoshan‐Barmatz et al ., ), neurodegeneration (Rodriguez et al ., ; Rao et al ., ; Kalani et al ., ) and ischaemia (Balderas et al ., ; Testai et al ., ; Smith et al ., ). In the present review, we discuss the recent developments in the field of mitochondrial ion channels, especially from the point of view of their pharmacological targeting.…”

Evidence of BKCa Channelopathy-Driven Breast Cancer Metastasis to Brain

“…Ion channels and transporters are some of the key modulators of cancer progression in hostile tumor microenvironment that includes hypoxia. It has been suggested that modulation of ion channels by the hypoxic environment may contribute to the aggressive phenotype observed in GBM cells residing in a hypoxic environment [22]. In hostile microenvironment such as hypoxia, BK Ca channels are modulated to aid cancer cell invasion and neovascularization.…”

Transcriptional repression of human epidermal growth factor receptor 2 by ClC‐3 Cl−/H+ transporter inhibition in human breast cancer cells

“…ClC‐1, ‐2, ‐Ka, and ‐Kb function as Cl − channels that localize at the plasma membrane, whereas ClC‐3 to ‐7 function as Cl − /H + transporters that distribute at intracellular vesicles such as endosomes/lysosomes and contribute to their acidification . Ion channels/transporters are expressed in several organelles such as mitochondria, endoplasmic reticulum, and endosomes, and intracellular ion channels play a role in the control of cancer development and progression . Intracellular ClC‐3 is highly expressed in metastatic cancer cells, accelerates cell migration, and contributes to the acquisition of resistance to chemotherapeutic drugs and anti‐HER2 therapies .…”