The retinoblastoma protein (Rb) as an anti-apoptotic factor: expression of Rb is required for the anti-apoptotic function of BAG-1 protein in colorectal tumour cells

Collard, Tracey J; Urban, Bettina C.; Patsos, HA; Hague, Angela; Townsend, Paul A.; Paraskeva, Christos; Williams, Ann C.

doi:10.1038/cddis.2012.142

Cited by 35 publications

(25 citation statements)

References 42 publications

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“…RB has been shown be function as an anti-apoptotic factor(28) and microarray analysis demonstrated that induction of pro-apoptotic transcripts in the setting of RB depletion (Supplemental Figure 2). Many of the altered gene transcripts are pro-apoptotic genes regulated via NFκB including DR4, TRAIL, RIP1 Fas, FasL, MYC, NOTCH2 and PLK3(29).…”

Section: Resultsmentioning

confidence: 99%

The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness

Thangavel

Boopathi

Ciment

et al. 2014

Clinical Cancer Research

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Purpose Perturbations in the RB pathway are overrepresented in advanced prostate cancer; RB loss promotes bypass of first line hormone therapy. Conversely, preliminary studies suggested that RB-deficient tumors may become sensitized to a subset of DNA damaging agents. Here, the molecular and in vivo consequence of RB status was analyzed in models of clinical relevance. Experimental Design Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts. Results Loss of RB enhanced the radioresponsiveness of both hormone sensitive and castrate resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. RB loss led to alteration in DNA damage repair and activation of the NFκB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with ionizing radiation (p<0.05). Conclusions Loss of RB confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of RB loss, but also credential RB status as a putative biomarker for predicting response to radiation therapy.

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Section: Resultsmentioning

confidence: 99%

The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness

Thangavel

Boopathi

Ciment

et al. 2014

Clinical Cancer Research

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“…pRB hyperphosphorylation by cyclin/CDK complexes (mainly cyclin D and CDK 4/6) is a key event for the G1 to S phase transition [19], [20]. Previous studies from our research group and others [21], [22], [23], [24] have demonstrated that pRb has an anti-apoptotic effect in specific conditions: expression of a non-cleavable form of pRb prevented cell death induced by TNF-R1 activation in cultured fibroblasts and by lipopolysaccharide (LPS) and TNF-α exposure in gastrointestinal mucosa of mice [21], [22]. Seventy percent of all tumor types have changes in the pRB pathway, with the nature of the change varying across types [14], [25], [26].…”

Section: Introductionmentioning

confidence: 80%

Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells

Soletti

Biasoli

Rodrigues

et al. 2017

Translational Oncology

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Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Current chemotherapy regimens include a combination of 5-fluorouracil (5-FU) and cisplatin, but more efficient therapy strategies are needed to increase 5-year survival. Alterations in the signaling pathway of the tumor suppressor gene Rb-1, which encodes a phosphoprotein (pRB) that negatively regulates the G1/S transition of the cell cycle, are present in 70% of all tumors, but its role in esophageal cancer is still unclear. Most of these are alterations leading to up-regulation of the activity of cyclin-dependent kinases (CDKs) to phosphorylate pRB, which suggests that keeping the wild type pRB phosphorylated might be advantageous. Besides proliferation, pRB also regulates apoptosis induced by tumor necrosis factor-alpha (TNF-α) and DNA-damage. We investigated the status of phosphorylation of pRB along esophageal tumorigenesis stages, as well as whether hyperphosphorylation of pRB could suppress apoptosis induced by cisplatin, 5-FU, or TNF-α in esophageal cancer cells. pRB phosphorylation increased progressively from normal esophageal tissue to metaplasia and adenocarcinoma, suggesting that pRB phosphorylation increases along esophageal tumor stages. When RB-1 was knocked down or CDK inhibitors reduced the levels of phosphorylated pRB, opposite apoptotic effects were observed, depending on the combination of drugs tested: whereas TNF-α- and cisplatin-induced apoptosis increased, 5-FU-induced apoptosis decreased. Taken together, these data suggest that pRB plays a role in esophageal adenocarcinoma and that, depending on the type of anti-cancer treatment, combining CDK inhibitors and chemotherapy has the potential to increase the sensitivity of esophageal cancer cells to cell death.

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“…Rb is typically not mutated in colorectal cancer cells [66]. However, during cell cycle G1/S transition Rb is phosphorylated and inactivated [63,64]; thus, it is possible that it is during this time that Wnt hyperactivation by histone deacetylase inhibitors induces colorectal cancer cell apoptosis.…”

Section: Rb Wnt Hyperactivation and Apoptosismentioning

confidence: 99%

Hypothesis: Retinoblastoma protein inactivation mediates effects of histone deacetylase inhibitor-induced Wnt hyperactivation in colorectal cancer cells

Bordonaro¹

2020

J. Cancer

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Butyrate, a product of dietary fiber and a histone deacetylase inhibitor, induces apoptosis of colorectal cancer cells; this effect of butyrate is in part mediated by its ability to hyperactivate Wnt signaling, and may in part explain the preventive action of dietary fiber against colorectal cancer. However, the mechanisms by which Wnt hyperactivation promotes apoptosis are unknown. Inactivation of the retinoblastoma tumor suppressor occurs in some cancers and can lead to context-dependent cell proliferation or cell death/apoptosis. The function of retinoblastoma protein (Rb) in normal cells is modulation of cell cycle; inactivation of Rb allows for cell cycle progression and, hence, cell proliferation. Wnt signaling is upregulated in a variety of cancers, and deregulated Wnt signaling is a key initiating event in most cases of sporadic colorectal cancer. It has been shown that Wnt signaling activated by APC inactivation can synergize with the inactivation of Rb to induce apoptosis in a manner mediated by increased TORC1 activity, leading to induced metabolic and energy stress. Rb is typically not inactivated in colorectal cancer; however, Rb is phosphorylated and deactivated during cell cycle G1/S transition. This manuscript posits that it is during this time that butyrate/histone deacetylase inhibitor-induced Wnt hyperactivation induces apoptosis in colorectal cancer cells. Thus, the inactivation of Rb in cell cycle progression may synergize with Wnt hyperactivation to induce apoptosis in response to histone deacetylase inhibitors. The hypothesis is that hyperactivation of Wnt signaling enhances colorectal cancer cell apoptosis via the interaction between upregulated Wnt signaling and inactivated Rb during cell cycle progression. This paper discusses this hypothesis and offers initial experimental approaches for testing the hypothesis. A better understanding of how histone deacetylase inhibitors induce colorectal cancer cell apoptosis through hyperactivation of Wnt signaling, and of cross-talk between repression of cell cycle and induction of apoptosis that occurs with treatment with histone deacetylase inhibitors, can assist in the development of novel therapies for colorectal cancer.

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The retinoblastoma protein (Rb) as an anti-apoptotic factor: expression of Rb is required for the anti-apoptotic function of BAG-1 protein in colorectal tumour cells

Cited by 35 publications

References 42 publications

The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness

The Retinoblastoma Tumor Suppressor Modulates DNA Repair and Radioresponsiveness

Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells

Hypothesis: Retinoblastoma protein inactivation mediates effects of histone deacetylase inhibitor-induced Wnt hyperactivation in colorectal cancer cells

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