TY - JOUR
T1 - AR-regulated TWEAK-FN14 pathway promotes prostate cancer bone metastasis
AU - Yin, JuanJuan
AU - Liu, Yen Nien
AU - Tillman, Heather
AU - Barrett, Ben
AU - Hewitt, Stephen
AU - Ylaya, Kris
AU - Fang, Lei
AU - Lake, Ross
AU - Corey, Eva
AU - Morrissey, Colm
AU - Vessella, Robert
AU - Kelly, Kathleen
PY - 2014/8/15
Y1 - 2014/8/15
N2 - The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKKβ-dependent, NFκB signaling activation. In human prostate cancer, upregulated FN14 expression was observed in more than half of metastatic samples. In addition, FN14 expression was correlated inversely with androgen receptor (AR) signaling output in clinical samples. Consistent with this, AR binding to the FN14 enhancer decreased expression. We show here that FN14 may be a survival factor in low AR output prostate cancer cells. Our results define one upstream mechanism, via FN14 signaling, through which the NFκB pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers.
AB - The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKKβ-dependent, NFκB signaling activation. In human prostate cancer, upregulated FN14 expression was observed in more than half of metastatic samples. In addition, FN14 expression was correlated inversely with androgen receptor (AR) signaling output in clinical samples. Consistent with this, AR binding to the FN14 enhancer decreased expression. We show here that FN14 may be a survival factor in low AR output prostate cancer cells. Our results define one upstream mechanism, via FN14 signaling, through which the NFκB pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers.
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U2 - 10.1158/0008-5472.CAN-13-3233
DO - 10.1158/0008-5472.CAN-13-3233
M3 - Article
C2 - 24970477
AN - SCOPUS:84905963664
SN - 0008-5472
VL - 74
SP - 4306
EP - 4317
JO - Cancer Research
JF - Cancer Research
IS - 16
ER -
