Bmi1 Enhances Tumorigenicity and Cancer Stem Cell Function in Pancreatic Adenocarcinoma

Proctor, Erica; Waghray, Meghna; Lee, Cheong; Heidt, David G.; Yalamanchili, Malica; Li, Chenwei; Bednar, Filip; Simeone, Diane M.

doi:10.1371/journal.pone.0055820

Cited by 96 publications

(69 citation statements)

References 37 publications

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“…As an oncogene, Bmi1 is abundantly expressed in many kinds of cancers and is correlated with multiple behaviors including tumorigenicity, drug resistance and cancer recurrence [24–26]. In our study, we found that a certain concentration range of gemcitabine promoted Bmi1 expression in pancreatic cancer cells.…”

Section: Discussionsupporting

confidence: 51%

Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine

et al. 2016

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As the standard therapy for pancreatic cancer, gemcitabine shows limited efficacy in pancreatic cancer patients because of chemoresistance. Aberrant expression of Bmi1 has been reported to activate multiple growth-regulatory pathways and confer anti-apoptotic abilities to many cancer cells. However, the role of Bmi1 in response of pancreatic cancer cells towards gemcitabine resistance remains elusive. In this study, we found that certain dose of gemcitabine treatment induced Bmi1 expression in pancreatic cancer cells. Knockdown of Bmi1 enhanced ROS production and promoted the cytotoxic effect of gemcitabine. The increased oxidative stress upon gemcitabine treatment could disrupt mitochondrial membrane and decrease mitochondrial membrane potential, eventually leading to apoptosis. Bmi1 inhibition also suppressed the activation of NF-κB signaling and the expressions of downstream molecules in pancreatic cancer cells treated with gemcitabine. Moreover, we observed Bmi1 inhibition sensitized the pancreatic xenograft tumors to gemcitabine in vivo. Taken together, our study demonstrated that Bmi1 could decrease the sensitivity of pancreatic cancer cells to gemcitabine through increasing oxidative stress and inhibiting NF-κB signaling, thus Bmi1 may serve as a promising target for sensitizing pancreatic cancer cells to chemotherapy.

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Section: Discussionsupporting

confidence: 51%

Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine

et al. 2016

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“…BMI1 is an important regulator of cancer stem cell (CSC) phenotype and is often overexpressed in cancer cells leading to resistance to therapy (10,16,22). While several studies have shown that BMI1 inhibition increased susceptibility to cytotoxic agents and radiotherapy, the role of BMI1 in radiation response, especially in breast cancer, remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Silencing BMI1 radiosensitizes human breast cancer cells by inducing DNA damage and autophagy

et al. 2017

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Overexpression of BMI1 in human cancer cells, a member of the polycomb group of repressive complexes, correlates with advanced stage of disease, aggressive clinico-pathological behavior, poor prognosis, and resistance to radiation and chemotherapy. Studies have shown that experimental reduction of BMI1 protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increased susceptibility to cytotoxic agents and radiation therapy. Although a role for BMI1 in cancer progression and its importance as a molecular target for cancer therapy has been established, information on the impact of silencing BMI1 in triple-negative breast cancer (TNBC) and its consequence on radiotherapy have not been well studied. Therefore, in the present study we investigated the potential therapeutic benefit of radiation therapy in BMI1-silenced breast cancer cells and studied the mechanism(s) of radiosensitization. Human MDA-MB-231 and SUM159PT breast cancer cells that were either stably transfected with a lentiviral vector expressing BMI1 shRNA (shBMI1) or control shRNA (shControl) or transient transfection with a BMI1-specific siRNA were used. Silencing of BMI1 resulted in marked reduction in BMI1 both at the mRNA and protein level that was accompanied by a significant reduction in cell migration compared to control cells. Further, BMI1 knockdown produced a marked enhancement of DNA damage as evidenced by Comet Assay and γH2AX foci, resulting in a dose-dependent radiosensitization effect. Molecular studies revealed modulation of protein expression that is associated with the DNA damage response (DDR) and autophagy pathways. Our results demonstrate that BMI1 is an important therapeutic target in breast cancer and suppression of BMI1 produces radiation sensitivity. Further, combining BMI1-targeted therapeutics with radiation might benefit patients diagnosed with TNBC.

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“…Sections were then de-waxed in xylene, rehydrated according to standard histopathologic procedures, and stained with hematoxylin and eosin. A blinded pathologist reviewed the pathology slides and evaluated for presence of tumor cells, degree of fibrosis by trichrome staining and Ki-67 (Abcam, Cambridge, MA; clone SP6; 1:200 dilution) and SHH (Millipore, clone EP1190Y) according to standard IHC procedures described previously (22). Stained samples were graded by two variables: percentage of stained cancer cells (0-100%) and the intensity of staining (0-3) on IHC.…”

Section: Methodsmentioning

confidence: 99%

Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma

Kim

Sahai

Abel

et al. 2014

Clinical Cancer Research

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271

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Background The hedgehog (HH) signaling pathway is a key regulator in tumorigenesis of pancreatic adenocarcinoma (PDA) and is up-regulated in PDA cancer stem cells (CSCs). GDC-0449 is an oral small-molecule inhibitor of HH pathway. This study assessed the effect of GDC-0449-mediated HH inhibition in paired biopsies, followed by combined treatment with gemcitabine, in patients with metastatic PDA. Methods Twenty-five patients were enrolled of which 23 underwent core biopsies at baseline and following 3 weeks of GDC-0449. On day 29, 23 patients started weekly gemcitabine while continuing GDC-0449. We evaluated GLI1 and PTCH1 inhibition, change in CSCs, Ki-67, fibrosis, and assessed tumor response, survival and toxicity. Results On pre-treatment biopsy, 75% of patients had elevated sonic hedgehog (SHH) expression. On post-treatment biopsy, GLI1 and PTCH1 decreased in 95.6% and 82.6% of 23 patients, fibrosis decreased in 45.4% of 22 and Ki-67 in 52.9% of 17 evaluable patients. No significant changes were detected in CSCs pre- and post-biopsy. The median progression-free and overall survival for all treated patients was 2.8 and 5.3 months. The response and disease control rate was 21.7% and 65.2%. No significant correlation was noted between CSCs, fibrosis, SHH, Ki-67, GLI1, PTCH1 (baseline values, or relative change on post-treatment biopsy) and survival. Grade >3 adverse events were noted in 56% of patients. Conclusion We show that GDC-0449 for 3 weeks leads to down-modulation of GLI1 and PTCH1, without significant changes in CSCs compared to baseline. GDC-0449 and gemcitabine was not superior to gemcitabine alone in the treatment of metastatic pancreatic cancer.

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Bmi1 Enhances Tumorigenicity and Cancer Stem Cell Function in Pancreatic Adenocarcinoma

Cited by 96 publications

References 37 publications

Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine

Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine

Silencing BMI1 radiosensitizes human breast cancer cells by inducing DNA damage and autophagy

Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma

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