Abstract
Actomyosin contractility regulates various cellular processes including proliferation and differentiation while dysregulation of actomyosin activity contributes to cancer development and progression. Previously, we have reported that actomyosin-generated tension at adherens junctions is required for cell density-dependent inhibition of proliferation of normal skin keratinocytes. However, it remains unclear how actomyosin contractility affects the hyperproliferation ability of cutaneous squamous cell carcinoma (cSCC) cells. In this study, we find that actomyosin activity is impaired in cSCC cells both in vitro and in vivo. External application of tensile loads to adherens junctions by sustained mechanical stretch attenuates the proliferation of cSCC cells, which depends on intact adherens junctions. Forced activation of actomyosin of cSCC cells also inhibits their proliferation in a cell-cell contact-dependent manner. Furthermore, the cell cycle arrest induced by tensile loading to adherens junctions is accompanied by epidermal differentiation in cSCC cells. Our results show that the degree of malignant properties of cSCC cells can be reduced by applying tensile loads to adherens junctions, which implies that the mechanical status of adherens junctions may serve as a novel therapeutic target for cSCC.
Highlights
The great significance of actomyosin cytoskeleton and actomyosin-generated tension in epithelia development, morphogenesis, and homeostasis is well appreciated
Samples of the tumor-free back skin and DMBA/tetradecanoyl-phorbol acetate (TPA)-induced skin tumors from wild-type FVB/N mice were immunohistochemically (IHC) stained for Ki-67, a cell proliferation marker (Gerdes et al, 1984), and myosin regulatory light chain (MLC) phosphorylated at Ser19 site, as the pS19-MLC level reflects the contractile activity of actomyosin (Riento and Ridley, 2003) (Figure 1A), wherein smooth and skeletal muscle cells were used as the internal positive control for pS19-MLC staining (Supplementary Figures S1A,B)
A high level of pS19-MLC in the superficial region coincided with almost exclusively Ki-67-negative cells, while in the deeper regions MLC phosphorylation was largely reduced and Ki-67-positive cells were abundant (Supplementary Figure S1C). These results demonstrate that the high proliferation ability is closely associated with the low actomyosin activity throughout normal keratinocytes, papilloma, and cutaneous squamous cell carcinoma (cSCC) cells in vivo, and suggest that the reduction in MLC phosphorylation first occurs at a relatively early stage of skin cancer development
Summary
The great significance of actomyosin cytoskeleton and actomyosin-generated tension in epithelia development, morphogenesis, and homeostasis is well appreciated. At AJs, the transmembrane protein E-cadherin binds trans-homophilically via its extracellular domain, which mediates adhesion between the neighboring cells. The homophilic binding of E-cadherin per se does not inhibit but promotes the proliferation of cells (Liu et al, 2006; Hirata et al, 2017), and actomyosingenerated tension at AJs is essential for CIP in normal human keratinocytes (Hirata et al, 2017). Neither of the studies directly compared the level of actomyosin contractility in cSCC cells against normal keratinocytes. It remains unclear whether and how the tensile status at AJs contributes to the malignant proliferation of cSCC cells
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