An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity

Abstract

It is widely accepted that canonical Wnt (cWnt) signaling is required for the differentiation of osteoprogenitors into osteoblasts. Furthermore, tumor-derived secretion of the cWnt-antagonist Dickkopf-1 (Dkk-1) is known to cause bone destruction, inhibition of repair and metastasis in many bone malignancies, but its role in osteosarcoma (OS) is still under debate. In this study, we examined the role of Dkk-1in OS by engineering its overexpression in the osteochondral sarcoma line MOS-J. Consistent with the known role of Dkk-1 in osteoblast differentiation, Dkk-1 inhibited osteogenesis by the MOSJ cells themselves and also in surrounding tissue when implanted in vivo. Surprisingly, Dkk-1 also had unexpected effects on MOSJ cells in that it increased proliferation and resistance to metabolic stress in vitro and caused the formation of larger and more destructive tumors than controls upon orthotopic implantation. These effects were attributed in part to upregulation of the stress response enzyme and cancer stem cell marker aldehyde-dehydrogenase-1 (ALDH1). Direct inhibition of ALDH1 reduced viability under stressful culture conditions, whereas pharmacological inhibition of cWnt or overexpression of ALDH1 had a protective effect. Furthermore, we observed that ALDH1 was transcriptionally activated in a c-Jun-dependent manner through a pathway consisting of RhoA, MAP-kinase-kinase-4 and Jun N-terminal Kinase (JNK), indicating that noncanonical planar cell polarity-like Wnt signaling was the mechanism responsible. Together, our results therefore demonstrate that Dkk-1 enhances resistance of OS cells to stress by tipping the balance of Wnt signaling in favor of the non-canonical Jun-mediated Wnt pathways. In turn, this results in transcriptional activation of ALDH1 through Jun-responsive promoter elements. This is the first report linking Dkk-1 to tumor stress resistance, further supporting the targeting of Dkk-1 not only to prevent and treat osteolytic bone lesions but also to reduce numbers of stress-resistant tumor cells.

The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation

“…Of note, we also observed Wnt3a induced Gata-3 expression and non-physiologic high concentrations of Dkk-1 (>50 ng/ml) inhibited Gata-3 expression similar to the previous report. There are signaling pathways identified which Dkk-1 utilizes other than the well-known canonical Wnt pathway (Fukuda et al, 2010; Krause et al, 2014). It is notable that Dkk-1 has a colipase domain in its carboxy-terminal region that is responsible for Wnt antagonist activity, but the function and role of the N-terminal domain of Dkk-1 is largely unknown (Brott and Sokol, 2002).…”

Maternal embryokines that regulate development of the bovine preimplantation embryo

“…Expressed in the bovine endometrium (24,88), DKK1 can bind to LRP5/6 and, in the presence of the transmembrane protein KREMEN, cause its internalization and destruction and thereby prevent formation of the WNT-FZD-LRP5/6 complex (86,89,90). In addition, DKK1 can activate the planar cell polarity pathway (91)(92)(93). Addition of DKK1 blocks the inhibitory actions of AMBMP on development (87).…”

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…Conversely, as despite Dkk-1 being a Wnt pathway inhibitor, this protein has been found upregulated in several human cancers, such as lung, esophageal, breast, myeloma multiple and gastric cancer [120][121][122][123] , indicating that Dkk-1 could has a potential oncogenic role in these tumors rather than acting as a tumor suppressor by antagonizing Wnt signaling. That elevation of Dkk-1 expression is likely to be caused by some epigenetic alterations including the loss of promoter methylation of the Dkk-1 gene [123,124] . Moreover, the oncogenic activities of Dkk-1 could be mediated, at least in part, by non-canonical Junmediated Wnt pathways activation.…”