Targeting Mechanoresponsive Proteins in Pancreatic Cancer: 4-Hydroxyacetophenone Blocks Dissemination and Invasion by Activating MYH14

Abstract

Metastasis is complex, involving multiple genetic, epigenetic, biochemical, and physical changes in the cancer cell and its microenvironment. Cells with metastatic potential are often characterized by altered cellular contractility and deformability, lending them the flexibility to disseminate and navigate through different microenvironments. We demonstrate that mechanoresponsiveness is a hallmark of pancreatic cancer cells. Key mechanoresponsive proteins, those that accumulate in response to mechanical stress, specifically nonmuscle myosin IIA (MYH9) and IIC (MYH14), a-actinin 4, and filamin B, were highly expressed in pancreatic cancer as compared with healthy ductal epithelia. Their less responsive sister paralogsmyosin IIB (MYH10), a-actinin 1, and filamin A-had lower expression differential or disappeared with cancer progression. We demonstrate that proteins whose cellular contributions are often overlooked because of their low abundance can have profound impact on cell architecture, behavior, and mechan-ics. Here, the low abundant protein MYH14 promoted metastatic behavior and could be exploited with 4-hydroxyacetophenone (4-HAP), which increased MYH14 assembly, stiffening cells. As a result, 4-HAP decreased dissemination, induced cortical actin belts in spheroids, and slowed retrograde actin flow. 4-HAP also reduced liver metastases in human pancreatic cancer-bearing nude mice. Thus, increasing MYH14 assembly overwhelms the ability of cells to polarize and invade, suggesting targeting the mechanoresponsive proteins of the actin cytoskeleton as a new strategy to improve the survival of patients with pancreatic cancer.Significance: This study demonstrates that mechanoresponsive proteins become upregulated with pancreatic cancer progression and that this system of proteins can be pharmacologically targeted to inhibit the metastatic potential of pancreatic cancer cells.

Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer

“…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 ]. By contrast, 4-HAP does not alter the biochemical properties of the NM IIA paralog.…”

“…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.…”

May mechanobiology work forcefully for you

“…Perhaps the cytoskeleton can be a target for anti-cancer strategies 8 ; but there are mechanobiological prejudices. Many ideas about how the cytoskeleton and myosin II work originated from insight about muscle and its contractile system, says Robinson.…”

Genomic Amplification and Functional Dependency of the Gamma Actin Gene ACTG1 in Uterine Cancer

“…While dysregulation of actomyosin genes is associated with diseases including cardiomyopathies [ 1 , 2 , 3 , 4 , 5 ], tumor-associated functions of actomyosin genes have been demonstrated in cancer models including colorectal, prostate, breast, ovarian, melanoma, pancreatic, and others [ 6 , 7 , 8 ]. In addition, recent studies indicate some actomyosin genes are potential target genes in metastatic cancers [ 9 ]. Functionally, mechanotransduction through actomyosin protein functions are key features of highly proliferative tumor cells, and their regulatory signaling pathways, such as RAS or G-protein coupled signaling, are indeed pro-tumorigenic [ 10 , 11 , 12 ].…”