Sam68 Allows Selective Targeting of Human Cancer Stem Cells

Benoit, Yannick D.; Mitchell, Ryan R.; Risueño, Ruth M.; Orlando, Luciana; Tanasijevic, Borko; Boyd, Allison L.; Aslostovar, Lili; Salci, Kyle R.; Shapovalova, Zoya; Russell, Jennifer; Eguchi, Masakatsu; Golubeva, Diana; Graham, Monica; Xenocostas, Anargyros; Trus, Michael; Foley, Ronan; Leber, Brian; Collins, Tony; Bhatia, Mickie

doi:10.1016/j.chembiol.2017.05.026

Cited by 40 publications

(77 citation statements)

References 57 publications

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“…One study reported that severe ER stress can block WNT protein processing and secretion [35]. Mechanistically, CWP disrupts interactions between CBP and β-catenin [36]. Consequently, CWP induces Sam68/CBP complex formation, which alters CBP/β-catenin-dependent transcription to promote apoptosis and differentiation [36].…”

Section: Discussionmentioning

confidence: 99%

The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway

Pak

Park

Kim

et al. 2019

J Exp Clin Cancer Res

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Background Androgen receptor (AR)-targeted treatments improve the survival of castration-resistant prostate cancer (CRPC) patients; however, secondary resistance to these agents ultimately occurs in virtually all patients. Therefore, alternative therapeutic targets are urgently needed. Since growing evidence demonstrates that WNT/β-catenin signaling plays an important role in CRPC, the antitumor activity and mechanism of action of CWP232291, a small molecule β-catenin inhibitor, were investigated in prostate cancer. Methods We assessed the antitumor activity of CWP232291 in prostate cancer cell lines and primary cells derived from CRPC patients. The effect of CWP232291 on apoptotic cell death, endoplasmic reticulum (ER) stress, cell viability, and WNT/β-catenin signaling was evaluated by flow cytometry, western blotting, luciferase reporter assay, and fluorescence microscopy. Antitumor efficacy was assessed in two CRPC xenograft mouse models. Results CWP232291 induced ER stress, resulting in upregulation of the proapoptotic protein CHOP and activation of caspase-3-dependent apoptosis. In addition, CWP232291 suppressed the expression of β-catenin by affecting WNT-dependent transcriptional activity, and downregulated AR and its splice variants in prostate cancer cells. Antitumor activity was observed in prostate cancer cells in vitro and ex vivo, and antitumor efficacy was observed in vivo. Conclusions Beyond providing preclinical evidence of therapeutic efficacy for the novel small molecule β-catenin inhibitor CWP232291 in CRPC, our results show that inducing ER stress and targeting WNT/β-catenin signaling may be a novel strategy against CRPC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1342-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway

Pak

Park

Kim

et al. 2019

J Exp Clin Cancer Res

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“…Tumour cell apoptosis − [127,141] − [38] or + [138] + [112,142] Cancer stem cells (CSC) + [69,72,135] − [143] + [144] EMT + [145][146][147][148] ? (in breast cancer) − (in lung and prostate carcinoma [149,150])…”

Section: Breast Cancer Progress Leptin Adiponectin Sam68mentioning

confidence: 99%

Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer

Maroni

2020

IJMS

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The most serious aspect of neoplastic disease is the spread of cancer cells to secondary sites. Skeletal metastases can escape detection long after treatment of the primary tumour and follow-up. Bone tissue is a breeding ground for many types of cancer cells, especially those derived from the breast, prostate, and lung. Despite advances in diagnosis and therapeutic strategies, bone metastases still have a profound impact on quality of life and survival and are often responsible for the fatal outcome of the disease. Bone and the bone marrow environment contain a wide variety of cells. No longer considered a passive filler, bone marrow adipocytes have emerged as critical contributors to cancer progression. Released by adipocytes, adipokines are soluble factors with hormone-like functions and are currently believed to affect tumour development. Src-associated in mitosis of 68 kDa (Sam68), originally discovered as a protein physically associated with and phosphorylated by c-Src during mitosis, is now recognised as an important RNA-binding protein linked to tumour onset and progression of disease. Sam68 also regulates splicing events and recent evidence reports that dysregulation of these events is a key step in neoplastic transformation and tumour progression. The present review reports recent findings on adipokines and Sam68 and their role in breast cancer progression and metastasis.

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“…Since its original identification as the first mitotic substrate and binding partner of Src tyrosine kinase, Sam68 has been reported to fulfill versatile functions in an array of important cellular processes including RNA metabolism, adipogenesis, gametogenesis, transcription, and others . More importantly, an increasing number of studies support an emerging role of Sam68 in tumor progression and development ; in particular, we recently uncovered that Sam68 is a key regulator of the DNA damage sensor PARP1 and plays an indispensable role in the very early cellular signaling cascade in response to DNA damage . Herein, we report that Sam68 regulates DNA damage‐initiated DNA repair and NF‐κB signaling pathways in keratinocytes and that Sam68 is crucial for the growth and survival of skin tumors in mice, which suggests a novel role of Sam68 in the development of NMSC and lends additional support to the pro‐oncogenic properties of Sam68.…”

Section: Discussionmentioning

confidence: 61%

“…Herein, we report that Sam68 regulates DNA damage‐initiated DNA repair and NF‐κB signaling pathways in keratinocytes and that Sam68 is crucial for the growth and survival of skin tumors in mice, which suggests a novel role of Sam68 in the development of NMSC and lends additional support to the pro‐oncogenic properties of Sam68. Our current work has added NMSC to the wide spectrum of cancers in which Sam68 expression is significantly elevated and correlates with tumor progression, including colon cancer, adult myeloid leukemia, oral tongue cancer, breast cancer, renal cell carcinoma, and now, nonmelanoma skin cancer (this study). The evidence herein reported suggests that Sam68, given a ubiquitous expression pattern, could serve as a general prognostic marker for multiple cancers.…”

Section: Discussionmentioning

confidence: 99%

Sam68 is required for the growth and survival of nonmelanoma skin cancer

Sun

Xia

et al. 2019

Cancer Medicine

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Although targeting DNA repair signaling pathways has emerged as a promising therapeutic for skin cancer, the relevance of DNA damage responses (DDR) in the development and survival of nonmelanoma skin cancer (NMSC), the most common type of skin cancer, remains obscure. Here, we report that Src‐associated substrate during mitosis of 68 kDa (Sam68), an early signaling molecule in DDR, is elevated in skin tumor tissues derived from NMSC patients and skin lesions from Gli2‐transgenic mice. Downregulation of Sam68 impacts the growth and survival of human tumor keratinocytes and genetic ablation of Sam68 delays the onset of basal cell carcinomas (BCC) in Gli2‐transgenic mice. Moreover, Sam68 plays a critical role in DNA damage‐induced DNA repair and nuclear factor kappa B (NF‐κB) signaling pathways in keratinocytes, hence conferring keratinocyte sensitivity to DNA damaging agents. Together, our data reveal a novel function of Sam68 in regulating DDR in keratinocytes that is crucial for the growth and survival of NMSC.

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Sam68 Allows Selective Targeting of Human Cancer Stem Cells

Cited by 40 publications

References 57 publications

The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway

The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway

Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer

Sam68 is required for the growth and survival of nonmelanoma skin cancer

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