Acidic pHe regulates cytoskeletal dynamics through conformational integrin β1 activation and promotes membrane protrusion

Li, Shun; Xiong, Niya; Peng, Yueting; Tang, Kai; Bai, Hongxia; Lv, Xiaoying; Jiang, Ying; Qin, Xiang; Yang, Hong; Wu, Chunhui; Zhou, Peng; Liu, Yiyao

doi:10.1016/j.bbadis.2018.04.019

Cited by 32 publications

(30 citation statements)

References 52 publications

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“…The fact that the acidic pH microenvironment induces tumor growth is an accepted fact. It is notable that cell signaling cascades in cancer cells, in part, are different from those in nonmalignant cells (LaMonte et al, 2013;Li et al, 2018). Knowing the true cellular signaling pathways in cancer cells contributes to finding more effective treatments.…”

Section: Autophagy Measurement Using Ao Stainingmentioning

confidence: 99%

Autophagic, apoptotic, and necrotic cancer cell fates triggered by acidic pH microenvironment

Rabiee

Tavakol

Barati

et al. 2018

Journal Cellular Physiology

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Cancer as a multifactorial and smart disease is now considered a challenging problem. Despite many investigations on drug discovery, it remains incurable, in part, due to insufficient understanding of its special mechanisms. For the first time, we collaterally investigated the effect of acidosis on the contribution of apoptosis, necrosis, and autophagy in MDA‐MB 231 cells. Our data showed that necrosis, apoptosis, and intracellular reactive oxygen species production drastically decreased from 48 to 72 hr while cell viability and autophagy increased along with a gap between the percentages. Eventually, the decrease of necrosis and apoptosis was related to upregulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and fatty acid synthetase, respectively. It seems that at the early stage of cancer progression, apoptosis is the main mechanism of cell mortality and afterward autophagy would be the main mechanism of cell survival. Therefore, at the acute phase of cancer, apoptotic inducer medications would be effective while at the chronic phase of cancer progression, autophagy inhibitor medication would be added as well. This eventually means that autophagy acts as both cell death and survival mechanisms at the onset of cancer progression with the approach towards cell survival. Besides other unknown cell survival mechanisms are involved in cell viability, except for apoptosis and necrosis inhibition and autophagy improvement. This study reiterates the inefficaciousness of autophagy inhibitor's medication at the onset of disease. It also emphasizes discovering other cell death mechanisms for cancer cell adaptation at the onset of disease with the aim of their targeting in cancer invasion therapy.

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Section: Autophagy Measurement Using Ao Stainingmentioning

confidence: 99%

Autophagic, apoptotic, and necrotic cancer cell fates triggered by acidic pH microenvironment

Rabiee

Tavakol

Barati

et al. 2018

Journal Cellular Physiology

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“…During this stage, the F-actin and the lamellipodium are the two crucial media linking the cellular behaviors and the mechanical properties. It has been reported that the acid extracellular pH induces the reorganization of F-actin cytoskeleton and facilitates the formation of lamellipodial protrusion [25], which can modulate the morphology and rigidity against the forces needed for cell migration [47]. It would be a key challenge and a great significance to study the correlation between the organization of F-actin structures and the viscoelasticity distribution in lamellipodium of living cancer cells under normal (pH 7.4) and acid (pH 6.5) microenvironments for revealing the nanomechanical mechanism of the cellular migration in metastasis.…”

Section: Topography and Viscoelasticity Of Cytoskeletons In Lamellipodium At Ph 74mentioning

confidence: 99%

“…The malignant degree of cancer cells is related to their migration speed, that is, the metastasis and invasiveness of cancer cells [21]. In particular, in the complex microenvironment of tumor tissues [22,23], the cancer cells will change the structure and topography of lamellipodia at an acid pH level, and then accelerate their metastasis [24,25]. However, the organization of the F-actin in lamellipodia under different pH microenvironments associated with the underlying relationship with the viscoelasticity and migration of living cancer cells remain unclear and is in urgent need to be fully interpreted.…”

Section: Introductionmentioning

confidence: 99%

Effect of F-Actin Organization in Lamellipodium on Viscoelasticity and Migration of Huh-7 Cells Under pH Microenvironments Using AM-FM Atomic Force Microscopy

et al. 2021

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Cytoskeleton is responsible for fundamental cellular processes and functions. The filamentous actin (F-actin) is a key constituent of the cytoskeleton system which is intrinsically viscoelastic and greatly determines the mechanical properties of cells. The organization and polymerization of F-actin are relevant to the viscoelasticity distribution and the migration of living cells responding to pH microenvironments. Recently, progression in various diseases such as cancers have been found that cellular migration is related to the alterations in the viscoelasticity of lamellipodium. However, the correlation among F-actin organization, viscoelastic properties and cellular migration of living cancer cells under different pH microenvironments are still poorly understood. Conventional experimental methods of optical microscopy and atomic force microscopy (AFM) can neither break the trade-off between resolution and rate in cytoskeleton imaging, nor achieve the structural characterization and the mechanical measurement simultaneously. Although multifrequency AFM with amplitude modulation-frequency modulation (AM–FM) enables us to probe both the surface topography and the viscoelasticity distribution of cells, it is difficult to image the cytoskeletal filaments with the diameter down to the scale of tens of nanometers. Here, we have improved the AM-FM AFM by employing the high damping of cell culture medium to increase the signal-to-noise ratio and achieve a stable imaging of F-actin with the resolution down to 50 nm under in situ microenvironment. The approach that can successfully visualize the structures of cytoskeletal filaments and measure the distribution of mechanical properties simultaneously enable us to understand the relationship between the organization of F-actin and the viscoelasticity of living Huh-7 cancer cells under different pH values. Our experimental results have demonstrated that, unlike the randomly distributed F-actin and the homogeneous viscoelasticity at the normal pH level of 7.4, the living Huh-7 cancer cells with the reduced pH level of 6.5 show highly oriented and organized F-actin along the lamellipodium direction associated with the significant gradient increase both in elasticity and viscosity, which are confirmed by immunofluorescence confocal microscopy. The F-actin organization and the gradient viscoelasticity of lamellipodium provide structural and mechanical understanding on the adhesion and migration of living cancer cells that undergo metastasis and malignant transformation.

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“…pH is a matrix property essential for invadopodium formation. Integrins mediate cellular cues and can act as pH sensors to regulate actin protrusions [206]. α5β1, αIIβ3 and αVβ3 modify their structural activation depending on pH, and acidic stimulation promotes integrin headpiece opening and FAK-SRC signaling induction [206].…”

Section: Microenvironment Factors Associated With Invadosome Formamentioning

confidence: 99%

“…Integrins mediate cellular cues and can act as pH sensors to regulate actin protrusions [206]. α5β1, αIIβ3 and αVβ3 modify their structural activation depending on pH, and acidic stimulation promotes integrin headpiece opening and FAK-SRC signaling induction [206]. During invadopodium maturation, cortactin phosphorylation recruits Na + /H + exchanger-1 (NHE1) to increase intracellular pH, which releases cofilin from cortactin molecules during invadopodium elongation [207].…”

Section: Microenvironment Factors Associated With Invadosome Formamentioning

confidence: 99%

Integrins: Moonlighting Proteins in Invadosome Formation

Peláez

Pariente

Pérez-Sala

et al. 2019

Cancers

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Invadopodia are actin-rich protrusions developed by transformed cells in 2D/3D environments that are implicated in extracellular matrix (ECM) remodeling and degradation. These structures have an undoubted association with cancer invasion and metastasis because invadopodium formation in vivo is a key step for intra/extravasation of tumor cells. Invadopodia are closely related to other actin-rich structures known as podosomes, which are typical structures of normal cells necessary for different physiological processes during development and organogenesis. Invadopodia and podosomes are included in the general term ‘invadosomes,’ as they both appear as actin puncta on plasma membranes next to extracellular matrix metalloproteinases, although organization, regulation, and function are slightly different. Integrins are transmembrane proteins implicated in cell–cell and cell–matrix interactions and other important processes such as molecular signaling, mechano-transduction, and cell functions, e.g., adhesion, migration, or invasion. It is noteworthy that integrin expression is altered in many tumors, and other pathologies such as cardiovascular or immune dysfunctions. Over the last few years, growing evidence has suggested a role of integrins in the formation of invadopodia. However, their implication in invadopodia formation and adhesion to the ECM is still not well known. This review focuses on the role of integrins in invadopodium formation and provides a general overview of the involvement of these proteins in the mechanisms of metastasis, taking into account classic research through to the latest and most advanced work in the field.

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Acidic pHe regulates cytoskeletal dynamics through conformational integrin β1 activation and promotes membrane protrusion

Cited by 32 publications

References 52 publications

Autophagic, apoptotic, and necrotic cancer cell fates triggered by acidic pH microenvironment

Autophagic, apoptotic, and necrotic cancer cell fates triggered by acidic pH microenvironment

Effect of F-Actin Organization in Lamellipodium on Viscoelasticity and Migration of Huh-7 Cells Under pH Microenvironments Using AM-FM Atomic Force Microscopy

Integrins: Moonlighting Proteins in Invadosome Formation

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