NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia

Kakiuchi, Seiji; Minami, Yosuke; Miyata, Yoshiharu; Mizutani, Yu; Goto, Hideaki; Kawamoto, Shinichiro; Yakushijin, Kimikazu; Kurata, Keiji; Matsuoka, Hiroshi; Minami, Hironobu

doi:10.3390/ijms18030486

Cited by 19 publications

(7 citation statements)

References 26 publications

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“…PF-04449913 treatment modulated the cell cycle regulation and self-renewal signaling, which in turn reduced the leukemia initiation potential of AML cells and enhanced sensitivity to chemotherapy, overcoming the resistance in the bone marrow microenvironment [ 182 ]. Recently, Kakiuchi et al reported that a novel SMO inhibitor, PF-913, impaired the self-renewal signature and cell cycle regulation of leukemic-stem-cell-like properties from AML patients, suggesting that PF-913 induced cell cycling in quiescent leukemia stem cells [ 180 ].…”

Section: Hedgehog Signaling In Cancers and Its Inhibitorsmentioning

confidence: 99%

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells

Sari

Phi

Jun

et al. 2018

Cells

142

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The Hedgehog (Hh) pathway is a signaling cascade that plays a crucial role in many fundamental processes, including embryonic development and tissue homeostasis. Moreover, emerging evidence has suggested that aberrant activation of Hh is associated with neoplastic transformations, malignant tumors, and drug resistance of a multitude of cancers. At the molecular level, it has been shown that Hh signaling drives the progression of cancers by regulating cancer cell proliferation, malignancy, metastasis, and the expansion of cancer stem cells (CSCs). Thus, a comprehensive understanding of Hh signaling during tumorigenesis and development of chemoresistance is necessary in order to identify potential therapeutic strategies to target various human cancers and their relapse. In this review, we discuss the molecular basis of the Hh signaling pathway and its abnormal activation in several types of human cancers. We also highlight the clinical development of Hh signaling inhibitors for cancer therapy as well as CSC-targeted therapy.

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Section: Hedgehog Signaling In Cancers and Its Inhibitorsmentioning

confidence: 99%

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells

Sari

Phi

Jun

et al. 2018

Cells

142

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“…The mechanism underlying the regulation of cancer stem cells by the HH signaling system is unclear, despite numerous studies on this topic. Homeobox protein NANOG (NANOG) is hypothesized to regulate cell self-renewal and chemotherapy resistance in several tumors and serve as a marker for certain cancer stem cells, such as hepatocellular carcinoma and head and neck tumors ( 13 – 16 ). Additionally, a previous study revealed that in myeloid leukemia tumors, NANOG is closely associated with and is a downstream factor of Gli ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Gli affects the stemness and prognosis of epithelial ovarian cancer via homeobox protein NANOG

Zhao

Pang

et al. 2020

Mol Med Rep

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Gli proteins are key transcription factors of the Hedgehog (HH) signaling pathway, which is associated with tumorigenesis and drug resistance. However, the role of the HH signaling pathway in epithelial ovarian cancer (EOC) remains unclear. Studies have demonstrated that in some tumors, homeobox protein NANOG (NANOG), a known stem cell marker, is a downstream effector of Gli. However, limited research has been conducted on the association between Gli and NANOG in EOC, particularly regarding their roles in the tumor stemness, such as tumor development, drug resistance and patient prognosis. Thus, the aim of the present study was to explore the aforementioned issues. In this study, Gli1, Gli2 and NANOG expression in EOC tissues was assessed using immunohistochemistry. Gene expression was also assessed using western blotting and reverse transcription-quantitative PCR in SKOV3 cells treated with a Gli inhibitor and an HH agonist. Furthermore, cell proliferation, colony-forming ability and cisplatin sensitivity were assessed using Cell Counting Kit-8 and colony formation assays. The results showed that both Gli1 and NANOG were associated with cisplatin resistance and EOC disease stage, while the nuclear expression of Gli2 was significantly associated with cisplatin resistance. Together, the expression of Gli and NANOG predicted poor patient prognosis. Targeting Gli with GANT61 impeded tumor proliferation, reversed cisplatin resistance and colony formation, and reduced NANOG expression. To conclude, Gli and NANOG may be effective indicators of platinum resistance and prognosis in EOC. Targeting Gli may reduce the stemness of ovarian cancer cell, which may be achieved via indirect targeting of NANOG.

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“…Melanomas critically require HH signaling [ 27 , 28 , 29 ], presumably with activated RAS-MAPK and AKT signaling cascades [ 27 ]. HH has been described to promote oncogenesis in leukemias [ 30 , 31 , 32 , 33 , 34 ], bladder cancer [ 35 ], and prostate cancer [ 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Widespread Expression of Hedgehog Pathway Components in a Large Panel of Human Tumor Cells and Inhibition of Tumor Growth by GANT61: Implications for Cancer Therapy

Réda

Vachtenheim

Vlčková

et al. 2018

IJMS

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The sonic Hedgehog/GLI signaling pathway (HH) is critical for maintaining tissue polarity in development and contributes to tumor stemness. Transcription factors GLI1–3 are the downstream effectors of HH and activate oncogenic targets. To explore the completeness of the expression of HH components in tumor cells, we performed a screen for all HH proteins in a wide spectrum of 56 tumor cell lines of various origin using Western blot analysis. Generally, all HH proteins were expressed. Important factors GLI1 and GLI2 were always expressed, only exceptionally one of them was lowered, suggesting the functionality of HH in all tumors tested. We determined the effect of a GLI inhibitor GANT61 on proliferation in 16 chosen cell lines. More than half of tumor cells were sensitive to GANT61 to various extents. GANT61 killed the sensitive cells through apoptosis. The inhibition of reporter activity containing 12xGLI consensus sites by GANT61 and cyclopamine roughly correlated with cell proliferation influenced by GANT61. Our results recognize the sensitivity of tumor cell types to GANT61 in cell culture and support a critical role for GLI factors in tumor progression through restraining apoptosis. The use of GANT61 in combined targeted therapy of sensitive tumors, such as melanomas, seems to be immensely helpful.

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NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia

Cited by 19 publications

References 26 publications

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells

Gli affects the stemness and prognosis of epithelial ovarian cancer via homeobox protein NANOG

Widespread Expression of Hedgehog Pathway Components in a Large Panel of Human Tumor Cells and Inhibition of Tumor Growth by GANT61: Implications for Cancer Therapy

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