Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis

Sun, Qing; Lesperance, Jacqueline; Wettersten, Hiromi I.; Luterstein, Elaine; DeRose, Yoko S.; Welm, Alana L.; Cheresh, David A.; Desgrosellier, Jay S.

doi:10.1172/jci93707

Cited by 42 publications

(46 citation statements)

References 52 publications

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“…Consistent with this model, previous studies have indicated that the degree of PUMA upregulation in response to EGFR TKIs in head and neck cancer cells is closely linked to the chemosensitivity of these cells, with ablation of PUMA signaling negating this sensitivity [23]. Other studies found that when exposed to the Bcl-2 homology 3 domains of PUMA, mitochondria isolated from tumor cells induced apoptotic pathways consistent with patient chemotherapy responses, suggesting a potential mechanism whereby PUMA mediates tumor cell death [24,25]. PUMA is thus a key biomarker for predicting tumor response and sensitivity to Cabozantinib both in CRC and a range of other cancers.…”

Section: Discussionsupporting

confidence: 65%

RETRACTED ARTICLE: Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3β/NF-κB signaling pathway

Yang

Zhang

et al. 2019

Cancer Gene Ther

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Cabozantinib is a multi-kinase inhibitor targeting MET, AXL, and VEGFR2, and has been approved for use in multiple malignancies. The means by which Cabozantinib acts to target colorectal cancer (CRC) cells remains poorly understood, and we sought to investigate how this drug disrupts cell growth in CRC cells and how it interacts to enhance the efficacy of other chemotherapeutic agents. In this study, we found that Cabozantinib activated a p65-dependent signaling pathway in response to both inhibition of AKT and activation of glycogen synthase kinase 3β (GSK3β), leading to upregulation of PUMA in CRC cells regardless of p53 activity. PUMA upregulation facilitates CRC apoptosis in response to Cabozantinib, which also acts synergistically with the chemotherapeutic agents Cetuximab and 5-FU to induce robust apoptosis in a PUMA-dependent manner. Eliminating PUMA expression ablated this apoptosis induced by Cabozantinib in xenograft mouse model. Our findings revealed that Cabozantinib acts to drive CRC cells apoptosis via a PUMA-dependent mechanism, thus identifying PUMA expression as a potential predictor of Cabozantinib efficacy and a potential novel therapeutic target.

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Section: Discussionsupporting

confidence: 65%

RETRACTED ARTICLE: Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3β/NF-κB signaling pathway

Yang

Zhang

et al. 2019

Cancer Gene Ther

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“…Slug expression and its role in distinct types of tumor initiating cells with low proteasome activity, high STAT3, or SOX2/OCT4 activity has not been investigated (Vlashi et al, 2013 ; Wei et al, 2014 ; Tang et al, 2015 ). However, Slug was shown to be important for survival of integrin αvβ3/Src-induced CSCs that also express E-cadherin and exist across BC subtypes (Sun et al, 2018 ). Mesenchymal CD44 + /CD24 −/low CSCs do not express E-cadherin but gain further tumor initiating capacity with the expression of the epithelial adhesion molecule EpCAM that marks “hybrid E/M” states (Dittmer, 2018 ).…”

Section: Slug and Breast Cancer Stem Cells: Which Ones And What Aboumentioning

confidence: 99%

Slug and E-Cadherin: Stealth Accomplices?

Sterneck

Poria

Balamurugan

2020

Front. Mol. Biosci.

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During physiological epithelial-mesenchymal transition (EMT), which is important for embryogenesis and wound healing, epithelial cells activate a program to remodel their structure and achieve a mesenchymal fate. In cancer cells, EMT confers increased invasiveness and tumor-initiating capacity, which contribute to metastasis and resistance to therapeutics. However, cellular plasticity that navigates between epithelial and mesenchymal states and maintenance of a hybrid or partial E/M phenotype appears to be even more important for cancer progression. Besides other core EMT transcription factors, the well-characterized Snail-family proteins Snail (SNAI1) and Slug (SNAI2) play important roles in both physiological and pathological EMT. Often mentioned in unison, they do, however, differ in their functions in many scenarios. Indeed, Slug expression does not always correlate with complete EMT or loss of E-cadherin (CDH1). For example, Slug plays important roles in mammary epithelial cell progenitor cell lineage commitment and differentiation, DNA damage responses, hematopoietic stem cell self-renewal, and in pathologies such as pulmonary fibrosis and atherosclerosis. In this Perspective, we highlight Slug functions in mammary epithelial cells and breast cancer as a "non-EMT factor" in basal epithelial cells and stem cells with focus reports that demonstrate co-expression of Slug and E-cadherin. We speculate that Slug and E-cadherin may cooperate in normal mammary gland and breast cancer/stem cells and advocate for functional assessment of such Slug + /E-cadherin low/+ (SNAI2 + /CDH1 low/+) "basal-like epithelial" cells. Thus, Slug may be regarded as less of an EMT factor than driver of the basal epithelial cell phenotype.

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“…EMT and TICs play critical roles in cancer metastasis and recurrence 44 , 45 , and are thus being exploited as therapeutic targets for metastatic breast cancer 14 , 46 . After acquiring mesenchymal characteristics following EMT, the pioneering tumor cells with stemness properties transendothelially migrate into the intratumoral microvessels and become circulating tumor cells (CTC), and the following extravasation enables these CTCs to disseminate and seed into distant organs to form new tumors 47 , 48 .…”

Section: Resultsmentioning

confidence: 99%

Emodin reduces Breast Cancer Lung Metastasis by suppressing Macrophage-induced Breast Cancer Cell Epithelial-mesenchymal transition and Cancer Stem Cell formation

et al. 2020

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Our previous studies demonstrated that the natural compound emodin blocks the tumor-promoting feedforward interactions between cancer cells and macrophages, and thus ameliorates the immunosuppressive state of the tumor microenvironment. Since tumor-associated macrophages (TAMs) also affect epithelial mesenchymal-transition (EMT) and cancer stem cell (CSC) formation, here we aimed to test if emodin as a neoadjuvant therapy halts breast cancer metastasis by attenuating TAM-induced EMT and CSC formation of breast cancer cells. Methods: Bioinformatical analysis was performed to examine the correlation between macrophage abundance and EMT/CSC markers in human breast tumors. Cell culture and co-culture studies were performed to test if emodin suppresses TGF-β1 or macrophage-induced EMT and CSC formation of breast cancer cells, and if it inhibits breast cancer cell migration and invasion. Using mouse models, we tested if short-term administration of emodin before surgical removal of breast tumors halts breast cancer post-surgery metastatic recurrence in the lungs. The effects of emodin on TGF-β1 signaling pathways in breast cancer cells were examined by western blots and immunofluorescent imaging. Results: Macrophage abundance positively correlates with EMT and CSC markers in human breast tumors. Emodin suppressed TGF-β1 production in breast cancer cells and macrophages and attenuated TGF-β1 or macrophage-induced EMT and CSC formation of breast cancer cells. Short-term administration of emodin before surgery halted breast cancer post-surgery metastatic recurrence in the lungs by reducing tumor-promoting macrophages and suppressing EMT and CSC formation in the primary tumors. Mechanistic studies revealed that emodin inhibited both canonical and noncanonical TGF-β1 signaling pathways in breast cancer cells and suppressed transcription factors key to EMT and CSC. Conclusion: Natural compound emodin suppresses EMT and CSC formation of breast cancer cells by blocking TGF-β1-mediated crosstalk between TAMs and breast cancer cells. Our study provides evidence suggesting that emodin harbors the potential for clinical development as a new effective and safe agent to halt metastatic recurrence of breast cancer.

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Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis

Cited by 42 publications

References 52 publications

RETRACTED ARTICLE: Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3β/NF-κB signaling pathway

RETRACTED ARTICLE: Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3β/NF-κB signaling pathway

Slug and E-Cadherin: Stealth Accomplices?

Emodin reduces Breast Cancer Lung Metastasis by suppressing Macrophage-induced Breast Cancer Cell Epithelial-mesenchymal transition and Cancer Stem Cell formation

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