Faculty Collaboration Database

Leukemia inhibitory factor can mediate Ras/Raf/MEK/ERK-induced growth inhibitory signaling in medullary thyroid cancer cells. Cancer Lett 2010 Nov 01;297(1):31-41

Date

06/24/2010

Pubmed ID

20570039

DOI

10.1016/j.canlet.2010.04.021

Scopus ID

2-s2.0-77956229707 (requires institutional sign-in at Scopus site)   44 Citations

Abstract

Medullary thyroid carcinoma (MTC) is a multiple endocrine neoplasia type 2 syndrome caused by mutations in extracellular receptor or intracellular kinase domains of the RET proto-oncogene. Activation of the Ras/Raf/MEK/ERK pathway can lead to growth arrest by secreting leukemia inhibitory factor (LIF) in MTC cells harboring a RET receptor domain mutation. Here, we report that Ras/Raf/MEK/ERK can also mediate, via LIF, growth inhibition in MTC cells harboring a RET kinase domain mutation. Ras/Raf/MEK/ERK activation was sufficient to induce growth inhibition and LIF expression in the human MTC line MZ-CRC-1. Presence of LIF-mediated signaling was determined by blocking the activity of culture medium conditioned by Raf-activated cells using anti-LIF neutralizing antibody. In addition, recombinant LIF effectively suppressed cell proliferation via cell cycle arrest in G0/G1 phase. Expression of dominant negative STAT3 abrogated LIF effects, indicating that LIF mediates its signaling through the JAK/STAT3 pathway. These results suggest that growth inhibition and activation of the autocrine/paracrine signaling through LIF/JAK/STAT may be a common response to Ras/Raf activation in different MTC types, and justify further evaluation of LIF as a potential anticancer agent for MTC.

Author List

Arthan D, Hong SK, Park JI

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Autocrine Communication
Carcinoma, Medullary
Cell Death
Cell Line, Tumor
Cell Proliferation
Culture Media, Conditioned
Extracellular Signal-Regulated MAP Kinases
Humans
Janus Kinases
Leukemia Inhibitory Factor
MAP Kinase Kinase Kinases
Mutation
Paracrine Communication
Proto-Oncogene Proteins c-raf
Proto-Oncogene Proteins c-ret
Recombinant Proteins
STAT3 Transcription Factor
Signal Transduction
Thyroid Neoplasms
Time Factors
Transfection
ras Proteins