Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism

Kobune, Masayoshi; Chiba, Hiroki; Kato, Junji; Kato, Kazunori; Nakamura, Kiminori; Kawano, Yutaka; Takada, Kohichi; Takimoto, Rishu; Takayama, Tetsuji; Hamada, Hirofumi; Niitsu, Yoshiro

doi:10.1158/1535-7163.mct-06-0684

Cited by 83 publications

(70 citation statements)

References 54 publications

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“…WNT-3, which typically activates WNT/␤-catenin signaling, was also shown to induce WNT/RHO signaling in an autocrine way in melanoma cells. In contrast to those findings on WNT/RAC signaling as a component of the WNT/␤-catenin pathway, WNT-3 was shown to activate RHO-A/ROCK signaling in an LRP5/ 6-independent manner (Kobune et al, 2007). In summary, this strongly indicates that WNTs, which generally activate WNT/␤-catenin signaling, are able to induce ␤-catenin-and LRP5/6-independent pathways in parallel.…”

Section: Wnt/rac and Wnt/rhocontrasting

confidence: 85%

See 1 more Smart Citation

International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors

Schulte¹

2010

Pharmacol Rev

200

231

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Section: Wnt/rac and Wnt/rhocontrasting

confidence: 85%

“…WNT-3A mediates cellular migration through DVL, RHO-A, and ROCK (Kishida et al, 2004;Endo et al, 2005;Kobune et al, 2007). Furthermore, RAC and the GEF DOCK4 are required for WNT/ ␤-catenin signaling, more precisely for the nuclear translocation of ␤-catenin (Upadhyay et al, 2008;Wu et al, 2008).…”

Section: Wnt/rac and Wnt/rhomentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors

Schulte¹

2010

Pharmacol Rev

200

231

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“…20 Moreover, ZOL inhibited small G-proteins, 20 which suggests that ZOL may play an indirect role in chemoresistence. 21 Bisphosphonates also have demonstrated synergistic cytotoxic or cytostatic effects when administered in combination with chemotherapy agents. 17,[22][23][24][25][26][27][28][29][30][31][32][33] In human primary BC cells, concomitant exposure to ibandronate or ZOL plus cyclophosphamide combined with methotrexate and 5-fluorouracil or epirubicin combined with cyclophosphamide, paclitaxel, or docetaxel enhanced the cytostatic effects compared with chemotherapy alone.…”

Section: Direct Anticancer Effectsmentioning

confidence: 99%

Zoledronic acid use in cancer patients

Coleman

Cook

Hirsh

et al. 2010

Cancer

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Bone is the most common site for metastasis from solid tumors, and the majority of patients will develop bone metastases during the natural course of their disease. Bisphosphonates are an effective treatment for preventing skeletal-related events in patients with bone metastases and may preserve functional independence and quality of life. Although several bisphosphonates have been investigated in patients with solid tumors, only zoledronic acid (ZOL) is approved by the US Food and Drug Administration and the European Medicines Agency for preventing skeletalrelated events in patients across a broad range of solid tumors. In addition, bisphosphonates, notably ZOL, prevent cancer treatment-induced bone loss in breast and prostate cancer patients who are receiving endocrine therapy. It also has been demonstrated that ZOL directly and indirectly inhibits cancer cell growth in vitro and growth and tumorigenesis in animal model systems. These properties may produce clinically meaningful benefits. In recent clinical studies in patients with cancer, ZOL improved overall and prolonged disease-free survival. Ongoing clinical trials in patients with solid tumors will provide further insight into the potential of ZOL to prevent distant metastases and improve survival. Cancer 2011;117:11-23. V C 2010 American Cancer Society.KEYWORDS: adjuvant setting, bisphosphonate, bone metastases, cancer, survival, zoledronic acid.During the progression of cancer, many patients will develop distant metastases, for which a common site is bone. 1For example, an estimated 75% of patients with advanced breast cancer (BC) or prostate cancer (PC), and 40% of patients with advanced lung cancer (LC) develop bone metastases.2,3 Without bone-targeted therapies, most patients with bone metastases will experience potentially debilitating skeletal-related events (SREs), such as pathologic fractures, spinal cord compression, the need for surgery or palliative radiotherapy to bone, or hypercalcemia of malignancy.1 These SREs can have debilitating consequences and reduce quality of life and survival. 4 Moreover, declines in performance status resulting from SREs could preclude the receipt of chemotherapy and radiotherapy by patients with some solid tumors. 5Bisphosphonates, which are inhibitors of osteoclast-mediated bone resorption, currently are the standard of care for preventing SREs in patients with bone metastases.6 Several bisphosphonates currently are approved by the US Food and Drug Administration and the European Medicines Agency for preventing SREs in patients with metastatic BC and multiple myeloma (MM). In addition, the nitrogen-containing bisphosphonate (N-BP) zoledronic acid (ZOL) has received widespread regulatory approval for patients with bone involvement from PC, LC, and the entire range of other solid tumors (OSTs). 6 In randomized phase 3 trials, ZOL (4 mg intravenously [iv] every 3 to 4 weeks [monthly]) demonstrated significant efficacy in delaying the onset and reducing the risk of SREs and in palliating bone pain, reducing analges...

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“…Recent studies have reported that altered WNT/β-catenin signaling can change the sensitivity of tumor cells to therapeutic drugs (21)(22)(23)(24), yet potential roles for β-catenin-independent WNT signaling in drug resistance are not well understood. In the present study, we found that WNT5A protein and transcript levels were dramatically increased in BRAFi-resistant cell lines and in patient tumors.…”

Section: Introductionmentioning

confidence: 99%

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

et al. 2014

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About half of all melanomas harbor a mutation that results in a constitutively active BRAF kinase mutant (BRAF V600E/K ) that can be selectively inhibited by targeted BRAF inhibitors (BRAFis). While patients treated with BRAFis initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. Here, we observed marked elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein were also elevated in BRAFiresistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction of endogenous WNT5A in melanoma decreased cell growth, increased apoptosis in response to BRAFi challenge, and decreased the activity of prosurvival AKT signaling. Conversely, overexpression of WNT5A promoted melanoma growth, tumorigenesis, and activation of AKT signaling. Similarly to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibited growth, sensitized melanoma cells to BRAFi, and reduced AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which promotes AKT signaling through FZD7 and RYK, leading to increased growth and therapeutic resistance. Furthermore, increased WNT5A expression in BRAFi-resistant melanomas correlates with a specific transcriptional signature, which identifies potential therapeutic targets to reduce clinical BRAFi resistance.

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Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism

Abstract: Adhesion of myeloma cells to bone marrow stromal cells is now considered to play a critical role in chemoresistance.

Cited by 83 publications

References 54 publications

International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors

International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors

Zoledronic acid use in cancer patients

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

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