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Cancers 2016, 8(5), 49; doi:10.3390/cancers8050049

In Hyperthermia Increased ERK and WNT Signaling Suppress Colorectal Cancer Cell Growth

1
Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA 18509, USA
2
Department of Cell Biology, Fukuoka University, Fukuoka 814-0180, Japan
*
Author to whom correspondence should be addressed.
Academic Editors: Renée van Amerongen and Walter Birchmeier
Received: 5 January 2016 / Revised: 15 April 2016 / Accepted: 10 May 2016 / Published: 14 May 2016
(This article belongs to the Special Issue Wnt Signaling in Cancer)
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Abstract

Although neoplastic cells exhibit relatively higher sensitivity to hyperthermia than normal cells, hyperthermia has had variable success as an anti-cancer therapy. This variable outcome might be due to the fact that cancer cells themselves have differential degrees of sensitivity to high temperature. We hypothesized that the varying sensitivity of colorectal cancer (CRC) cells to hyperthermia depends upon the differential induction of survival pathways. Screening of such pathways revealed that Extracellular Signal-Regulated Kinase (ERK) signaling is augmented by hyperthermia, and the extent of this modulation correlates with the mutation status of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Through clonal growth assays, apoptotic analyses and transcription reporter assays of CRC cells that differ only in KRAS mutation status we established that mutant KRAS cells are more sensitive to hyperthermia, as they exhibit sustained ERK signaling hyperactivation and increased Wingless/Integrated (WNT)/beta-catenin signaling. We propose that whereas increased levels of WNT and ERK signaling and a positive feedback between the two pathways is a major obstacle in anti-cancer therapy today, under hyperthermia the hyperinduction of the pathways and their positive crosstalk contribute to CRC cell death. Ascertaining the causative association between types of mutations and hyperthermia sensitivity may allow for a mutation profile-guided application of hyperthermia as an anti-cancer therapy. Since KRAS and WNT signaling mutations are prevalent in CRC, our results suggest that hyperthermia-based therapy might benefit a significant number, but not all, CRC patients. View Full-Text
Keywords: Hyperthermia; colorectal cancer; KRAS; ERK; WNT Hyperthermia; colorectal cancer; KRAS; ERK; WNT
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Bordonaro, M.; Shirasawa, S.; Lazarova, D.L. In Hyperthermia Increased ERK and WNT Signaling Suppress Colorectal Cancer Cell Growth. Cancers 2016, 8, 49.

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