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Review
. 2020 Jul 3;12(7):1780.
doi: 10.3390/cancers12071780.

Mechanosensitive Piezo Channels in Cancer: Focus on altered Calcium Signaling in Cancer Cells and in Tumor Progression

Dario De Felice  1 , Alessandro Alaimo  1
Affiliations
Review

Mechanosensitive Piezo Channels in Cancer: Focus on altered Calcium Signaling in Cancer Cells and in Tumor Progression

Dario De Felice et al. Cancers (Basel). .

Abstract

Mechanotransduction, the translation of mechanical stimuli into biological signals, is a crucial mechanism involved in the function of fundamentally all cell types. In many solid tumors, the malignant transformation is often associated with drastic changes in cell mechanical features. Extracellular matrix stiffness, invasive growth, and cell mobility are just a few hallmarks present in cancer cells that, by inducing mechanical stimuli, create positive feedbacks promoting cancer development. Among the molecular players involved in these pathophysiological processes, the mechanosensitive Ca2+-permeable Piezo channels have emerged as major transducers of mechanical stress into Ca2+ dependent signals. Piezo channels are overexpressed in several cancers, such as in breast, gastric, and bladder, whereas their downregulation has been described in other cancers. Still, the roles of mechanosensitive Piezos in cancer are somewhat puzzling. In this review, we summarize the current knowledge on the pathophysiological roles of these Ca2+-permeable channels, with special emphasis on their functional involvement in different cancer types progression.

Keywords: calcium signaling; cancer progression; mechanotransduction; piezo channels.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanical and pharmacological modulation of Piezo1 channels. Mechanosensitive Piezo1 channels expressed on the plasma membrane are gated by various mechanical stimuli (black arrows). Channel activation allows a Ca2+ influx (blue spheres) into the cytoplasm which mediates countless cell responses. Piezo1 may be pharmacologically activated by agonists (blue arrows) or inhibited by channel pore blockers, competitive antagonists, and peptides, which distort the membrane mechanical properties (red inhibitory arrows). Structural data for Piezo1 channel were taken from Protein Data Bank (accession code: 3JAC) and created with BioRender.com.
Figure 2
Figure 2
Piezo1 mediates the stretch-induced progression of prostate cancer. The mechanical gating of the overexpressed Piezo1 stimulates Ca2+ influx (blue spheres), which triggers the activation of both Akt and mTOR, finally upregulating the expression of the cell cycle key players cyclin D1 and CDK4. These intracellular signal transduction cascades may be responsible for cell cycle progression, cell proliferation, and migration, thus, may support the progression of prostate cancer. Adapted from reference [83]. Created with BioRender.com.
Figure 3
Figure 3
Tumor tissue stiffening activates Piezo1 promoting glioma aggressiveness. Tumor tissue stiffening represents the mechanical stimuli which activates Piezo1 facilitating Ca2+ influx (blue spheres) into cytoplasm. Consequently, intracellular Ca2+ increase, directly or indirectly, activates the integrin-focal adhesion signaling, stimulates cell proliferation and modulates the extracellular matrix remodeling. Besides, the enhanced expression of Piezo1 channels reinforces the mechanosensitivity of the tumor cells, creating a feedforward mechanism which leads to a further glioma progression. Adapted from reference [86]. Created with BioRender.com.
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