4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis

Bryan, Darren S.; Stack, Melinda E.; Krysztofiak, Katarzyna; Cichoń, Urszula; Thomas, Dustin; Surcel, Alexandra; Schiffhauer, Eric S.; Beckett, Michael A.; Khodarev, Nikolai N.; Xue, Li; Poli, Elizabeth C.; Pearson, Alexander T.; Posner, Mitchell C.; Robinson, Douglas N.; Rock, Ronald S.; Weichselbaum, Ralph R.

doi:10.1073/pnas.2014639117

Cited by 28 publications

(25 citation statements)

References 54 publications

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“…Inhibition of either NM II or its upstream activator, ROCK, induces outgrowth of actin-rich protrusions from the Caco-2 cyst surface, eventuating in the collective cancer cell invasion of the surrounding matrix [ 111 , 114 ]. Consistent with these findings, a pharmacologic activator of actomyosin-dependent contractility, 4-hydroxyacetophenone, specifically targeting the NM IIB and NM IIC isoforms, inhibits invasion of HCT116 cells in vitro and attenuates metastatic spread of HCT116 cell xenografts in nude mice [ 115 ]. The described conflicting roles of NM II in regulating planar migration and 3-D hydrogel invasion of CRC cells likely reflect distinct functions of this cytoskeletal motor under different physical properties of the cell environment.…”

Section: Conventional Myosinsmentioning

confidence: 81%

“…Accumulating evidence about NM II inhibition in metastatic cancer cells [ 15 , 115 , 171 , 181 ] prompted a search for small molecular NM II activators with anti-metastatic properties. This search resulted in identification of 4-hydroxyacetophenone (4-HAP), a compound that activates NM IIB and NM IIC isoforms by increasing the assembly of their heavy chains independently of RMLC phosphorylation [ 171 , 181 ].…”

Section: Pharmacologic Modulators Of Myosin Activity: Are They Suimentioning

confidence: 99%

“…Activation of NM IIB and NM IIC with 4-HAP increases stiffness and reduces adhesion and migration of pancreatic and colon cancer cells in vitro [ 115 , 171 ]. Importantly, this NM II activator attenuates metastasis of pancreatic and colon cancer cells engrafted in nude mice [ 115 , 171 ]. Despite these encouraging data, it remains unclear whether 4-HAP could serve as a promising pro-drug for CRC-targeting therapy.…”

Section: Pharmacologic Modulators Of Myosin Activity: Are They Suimentioning

confidence: 99%

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Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Naydenov

Lechuga

Huang

et al. 2021

Cancers

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Colorectal cancer (CRC) remains the third most common cause of cancer and the second most common cause of cancer deaths worldwide. Clinicians are largely faced with advanced and metastatic disease for which few interventions are available. One poorly understood aspect of CRC involves altered organization of the actin cytoskeleton, especially at the metastatic stage of the disease. Myosin motors are crucial regulators of actin cytoskeletal architecture and remodeling. They act as mechanosensors of the tumor environments and control key cellular processes linked to oncogenesis, including cell division, extracellular matrix adhesion and tissue invasion. Different myosins play either oncogenic or tumor suppressor roles in breast, lung and prostate cancer; however, little is known about their functions in CRC. This review focuses on the functional roles of myosins in colon cancer development. We discuss the most studied class of myosins, class II (conventional) myosins, as well as several classes (I, V, VI, X and XVIII) of unconventional myosins that have been linked to CRC development. Altered expression and mutations of these motors in clinical tumor samples and their roles in CRC growth and metastasis are described. We also evaluate the potential of using small molecular modulators of myosin activity to develop novel anticancer therapies.

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Section: Conventional Myosinsmentioning

confidence: 81%

Section: Pharmacologic Modulators Of Myosin Activity: Are They Suimentioning

confidence: 99%

Section: Pharmacologic Modulators Of Myosin Activity: Are They Suimentioning

confidence: 99%

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Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Naydenov

Lechuga

Huang

et al. 2021

Cancers

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“…NMMII and PM-smACSK could be a signaling hub linking execution of cell proliferation, migration and apoptosis to signaling pathways controlling activities of ion channels and transporters. NMMII isoforms appear to regulate the metastatic potential of cancer cells and, thus, to be novel therapeutic targets [ 150 , 151 , 152 ]. Our hypothesis on NMMII as a key player in cell volume sensing broadens the spectrum of effects of NMMII in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Two Motors and One Spring: Hypothetic Roles of Non-Muscle Myosin II and Submembrane Actin-Based Cytoskeleton in Cell Volume Sensing

Barvitenko¹,

Aslam

Lawen

et al. 2021

IJMS

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Changes in plasma membrane curvature and intracellular ionic strength are two key features of cell volume perturbations. In this hypothesis we present a model of the responsible molecular apparatus which is assembled of two molecular motors [non-muscle myosin II (NMMII) and protrusive actin polymerization], a spring [a complex between the plasma membrane (PM) and the submembrane actin-based cytoskeleton (smACSK) which behaves like a viscoelastic solid] and the associated signaling proteins. We hypothesize that this apparatus senses changes in both the plasma membrane curvature and the ionic strength and in turn activates signaling pathways responsible for regulatory volume increase (RVI) and regulatory volume decrease (RVD). During cell volume changes hydrostatic pressure (HP) changes drive alterations in the cell membrane curvature. HP difference has opposite directions in swelling versus shrinkage, thus allowing distinction between them. By analogy with actomyosin contractility that appears to sense stiffness of the extracellular matrix we propose that NMMII and actin polymerization can actively probe the transmembrane gradient in HP. Furthermore, NMMII and protein-protein interactions in the actin cortex are sensitive to ionic strength. Emerging data on direct binding to and regulating activities of transmembrane mechanosensors by NMMII and actin cortex provide routes for signal transduction from transmembrane mechanosensors to cell volume regulatory mechanisms.

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“…It is the dynamic ability of being able to deform and simultaneously resist deformation that allows tumor cells to undergo the metastatic cascade. Therefore, a method to prevent metastasis for solid tumors would be to stiffen and decrease the cell shape change ability (8,13,(23)(24)(25)(26)(27).…”

Section: Introduction Cell Mechanics and Cancermentioning

confidence: 99%

Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to low therapeutic response rates and poor prognoses. Majority of patients present with symptoms post metastatic spread, which contributes to its overall lethality as the 4th leading cause of cancer-related deaths. Therapeutic approaches thus far target only one or two of the cancer specific hallmarks, such as high proliferation rate, apoptotic evasion, or immune evasion. Recent genomic discoveries reveal that genetic heterogeneity, early micrometastases, and an immunosuppressive tumor microenvironment contribute to the inefficacy of current standard treatments and specific molecular-targeted therapies. To effectively combat cancers like PDAC, we need an innovative approach that can simultaneously impact the multiple hallmarks driving cancer progression. Here, we present the mechanical properties generated by the cell’s cortical cytoskeleton, with a spotlight on PDAC, as an ideal therapeutic target that can concurrently attack multiple systems driving cancer. We start with an introduction to cancer cell mechanics and PDAC followed by a compilation of studies connecting the cortical cytoskeleton and mechanical properties to proliferation, metastasis, immune cell interactions, cancer cell stemness, and/or metabolism. We further elaborate on the implications of these findings in disease progression, therapeutic resistance, and clinical relapse. Manipulation of the cancer cell’s mechanical system has already been shown to prevent metastasis in preclinical models, but it has greater potential for target exploration since it is a foundational property of the cell that regulates various oncogenic behaviors.

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4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis

Cited by 28 publications

References 54 publications

Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

Two Motors and One Spring: Hypothetic Roles of Non-Muscle Myosin II and Submembrane Actin-Based Cytoskeleton in Cell Volume Sensing

Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications

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