TY - JOUR
T1 - 4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis
AU - Bryan, Darren S.
AU - Stack, Melinda
AU - Krysztofiak, Katarzyna
AU - Cichon, Urszula
AU - Thomas, Dustin G.
AU - Surcel, Alexandra
AU - Schiffhauer, Eric S.
AU - Beckett, Michael A.
AU - Khodarev, Nikolai N.
AU - Xue, Lai
AU - Poli, Elizabeth C.
AU - Pearson, Alexander T.
AU - Posner, Mitchell C.
AU - Robinson, Douglas N.
AU - Rock, Ronald S.
AU - Weichselbaum, Ralph R.
N1 - Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/9/8
Y1 - 2020/9/8
N2 - Metastases are the cause of the vast majority of cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the cancer cells to change shape and to navigate tissue barriers. Approaches that block this mechanical program represent new therapeutic avenues. We show that 4-hydroxyacetophenone (4-HAP) inhibits colon cancer cell adhesion, invasion, and migration in vitro and reduces the metastatic burden in an in vivo model of colon cancer metastasis to the liver. Treatment with 4-HAP activates nonmuscle myosin-2C (NM2C) (MYH14) to alter actin organization, inhibiting the mechanical program of metastasis. We identify NM2C as a specific therapeutic target. Pharmacological control of myosin isoforms is a promising approach to address metastatic disease, one that may be readily combined with other therapeutic strategies.
AB - Metastases are the cause of the vast majority of cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the cancer cells to change shape and to navigate tissue barriers. Approaches that block this mechanical program represent new therapeutic avenues. We show that 4-hydroxyacetophenone (4-HAP) inhibits colon cancer cell adhesion, invasion, and migration in vitro and reduces the metastatic burden in an in vivo model of colon cancer metastasis to the liver. Treatment with 4-HAP activates nonmuscle myosin-2C (NM2C) (MYH14) to alter actin organization, inhibiting the mechanical program of metastasis. We identify NM2C as a specific therapeutic target. Pharmacological control of myosin isoforms is a promising approach to address metastatic disease, one that may be readily combined with other therapeutic strategies.
KW - 4-hydroxyacetophenone
KW - Colorectal cancer
KW - Ex vivo motility
KW - Metastasis
KW - Nonmuscle myosin 2C
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UR - http://www.scopus.com/inward/citedby.url?scp=85090614124&partnerID=8YFLogxK
U2 - 10.1073/pnas.2014639117
DO - 10.1073/pnas.2014639117
M3 - Article
C2 - 32848073
AN - SCOPUS:85090614124
SN - 0027-8424
VL - 117
SP - 22423
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 36
ER -