Mechanoactivation of NOX2-generated ROS elicits persistent TRPM8 Ca signals that are inhibited by oncogenic KRas
AuthorPratt, Stephen J P
Lee, Rachel M
Chang, Katarina T
Hernández-Ochoa, Erick O
Annis, David A
Ory, Eleanor C
Thompson, Keyata N
Bailey, Patrick C
Mathias, Trevor J
Ju, Julia A
Vitolo, Michele I
Schneider, Martin F
Stains, Joseph P
Ward, Christopher W
Martin, Stuart S
JournalProceedings of the National Academy of Sciences of the United States of America
PublisherNational Academy of Sciences
MetadataShow full item record
AbstractChanges in the mechanical microenvironment and mechanical signals are observed during tumor progression, malignant transformation, andmetastasis. In this context, understanding themolecular details of mechanotransduction signaling may provide unique therapeutic targets. Here, we report that normal breast epithelial cells are mechanically sensitive, responding to transient mechanical stimuli through a two-part calcium signaling mechanism. We observed an immediate, robust rise in intracellular calcium (within seconds) followed by a persistent extracellular calcium influx (up to 30 min). This persistent calcium was sustained via microtubule-dependent mechanoactivation of NADPH oxidase 2 (NOX2)-generated reactive oxygen species (ROS), which acted on transient receptor potential cation channel subfamily M member 8 (TRPM8) channels to prolong calcium signaling. In contrast, the introduction of a constitutively active oncogenic KRas mutation inhibited the magnitude of initial calcium signaling and severely blunted persistent calcium influx. The identification that oncogenic KRas suppresses mechanically-induced calcium at the level of ROS provides a mechanism for how KRas could alter cell responses to tumor microenvironment mechanics and may reveal chemotherapeutic targets for cancer. Moreover, we find that expression changes in both NOX2 and TRPM8 mRNA predict poor clinical outcome in estrogen receptor (ER)-negative breast cancer patients, a population with limited available treatment options. The clinical and mechanistic data demonstrating disruption of this mechanically-activated calcium pathway in breast cancer patients and by KRas activation reveal signaling alterations that could influence cancer cell responses to the tumor mechanical microenvironment and impact patient survival.
Rights/TermsCopyright © 2020 the Author(s). Published by PNAS.
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/13993
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