Bcl-2 on the brink of breakthroughs in cancer treatment

Reed, John C.

doi:10.1038/cdd.2017.188

Cited by 49 publications

(35 citation statements)

References 16 publications

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“…Our findings indicate that the drug resistance in pediatric PTC, i.e., sorafenib-resistant patient-derived PTC cell, could be inhibited by lenvatinib, through the inhibition of the EMT-mediated FGFR signaling pathway and Bcl-2. It is a well-known fact that the anti-apoptotic factor and proto-oncogene Bcl-2 is a key player in the control of apoptosis [46][47][48]. These results resolutely showed that Bcl-2 is also involved in EMT, an essential mechanism in the drug resistance of pediatric PTC [49,50].…”

Section: Discussionmentioning

confidence: 69%

Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer

Kim

Park

et al. 2020

Cancers

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The incidence of papillary thyroid carcinoma (PTC) has been increasing worldwide. PTC is the most common type of differentiated thyroid cancer and usually shows good prognosis. However, some PTC is driven to advanced stage by epithelial-mesenchymal transition (EMT)-mediated drug resistance, which is particularly noticeable in pediatric patients. There are limited options for systemic treatment, necessitating development of new clinical approaches. Here, we aimed to clarify genetic differences due to age of patients with PTC, and thereby aid in developing novel therapeutics. Patients with biochemically and histologically confirmed PTC were included in this study. PTC cells were acquired from young and older patients showing drug resistance, and were compared via microarray analysis. Cellular proliferation and other properties were determined after treatments with lenvatinib and sorafenib. In vivo, tumor volume and other properties were examined using a mouse xenograft model. Lenvatinib-treated group showed obvious suppression of markers of anti-apoptosis, EMT, and the FGFR signaling pathway, compared with control and Sorafenib-treated group. In the xenograft models, lenvatinib treatment induced significant tumor shrinkage and blocked the proto-oncogene Bcl-2 (B cell lymphoma/leukemia gene-2) and FGFR signaling pathway, along with reduced levels of EMT markers, compared with control and Sorafenib-treated group. Our findings clarify the age-dependent characteristics of pediatric PTC, giving insights into the relationship between young age and poor prognosis. Furthermore, it provides a basis for developing novel therapeutics tailored to the age at diagnosis.

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Section: Discussionmentioning

confidence: 69%

Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer

Kim

Park

et al. 2020

Cancers

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“…Aberrant PI3K/Akt pathway signaling also inhibits apoptosis by upregulating the expression of B cell lymphoma 2 (Bcl-2) and decreasing the levels of apoptosis regulators such as p53 and the Bcl-2associated X [61,62] . Bcl-2 protects cancer cells against CTL-mediated cytotoxicity and is under the regulation of several oncogenic pathways, including the MAPK pathway [63,64] . Researchers in the past have identified Bcl-2 as a predictive marker of patient response to immunotherapy in clinical samples of metastatic renal cell carcinoma [65] , raising the possibility of targeting Bcl-2 to enhance the vulnerability of cancer cells to immunotherapies [66] .…”

Section: Anti-apoptotic Mechanismsmentioning

confidence: 99%

Cell-mediated immune resistance in cancer

Wang¹,

Hays²,

Rama³

et al. 2019

CDR

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The genetic and epigenetic aberrations that underlie immune resistance lead to tumors that are refractory to clinically established and experimental immunotherapies, including monoclonal antibodies and T cell-based therapies. From various forms of cytotoxic T cells to small molecule inhibitors that revamp the tumor microenvironment, these therapies have demonstrated notable responses in cancer models and a resistant subset of cancer patients, used both alone and in combination. However, even current approaches, such as those targeting checkpoint molecules, tumor ligands, and involving gene-related therapies, present a challenge in non-responding patients. In this perspective, we discuss the most common mechanisms of immune resistance, including tumor heterogeneity, tumor ligand and major histocompatibility complex modulation, anti-apoptotic pathways, checkpoint inhibitory ligands, immunosuppressive cells and factors in the tumor microenvironment, and activation-induced cell death. In addition, we discuss the strategies designed to circumvent these resistance pathways to showcase the potential of emerging technologies in battling the rise of resistance.

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“…c-Myc, a tumor stem cell differentiation-related factor, was markedly down-regulated in the SACC-83 and SACC-LM cells transfected with WHSC1-KD1 or WHSC1-KD2 compared to the control (p<0.05) ( Figure 4A and B). Survivin and Bcl-2, two anti-apoptotic factors (16,17), were significantly inhibited in the SACC-83 and SACC-LM cells transfected with WHSC1-KD1 or WHSC1-KD2 compared to the control (p<0.05) ( Figure 4B). Furthermore, cyclin B1, which is related to G 2 /M checkpoint (18), was also reduced in the SACC-83 and SACC-LM cells transfected with WHSC1-KD1 or WHSC1-KD2 compared to the control (p<0.05) ( Figure 4B).…”

Section: Whsc1 Expression Is Upregulated In Human Saccmentioning

confidence: 99%

Knockdown of Histone Methyltransferase WHSC1 Induces Apoptosis and Inhibits Cell Proliferation and Tumorigenesis in Salivary Adenoid Cystic Carcinoma

et al. 2019

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Background/Aim: Salivary adenoid cystic carcinoma (SACC) is the most common malignancy of the salivary gland with a poor prognosis and survival. The present study aimed to investigate the role of histone methyltransferase WHSC1 in SACC. Materials and Methods: Human SACC specimens were evaluated for WHSC1 expression by RT-PCR and immunohistochemistry. The effects of WHSC1 knockdown on SACC cells proliferation, cell cycle, clone and tumorsphere formation, and apoptosis as well as on the expression of related genes were examined. A xenograft mouse model of SACC was used to evaluate the in vivo effects of WHSC1 knockdown on SACC tumorigenesis. Results: WHSC1 expression was up-regulated in human SACC tissues (p<0.01). WHSC1 knockdown in SACC cells significantly inhibited cell proliferation, clone and tumorsphere formation (p<0.05). Cell distribution at the S and G 2 /M phases was significantly reduced by WHSC1 knockdown (p<0.05). WHSC1 knockdown significantly increased apoptosis of SACC cells (p<0.05). c-Myc, survivin, Bcl-2 and cyclin B1 genes were significantly down-regulated by WHSC1 knockdown cells (p<0.05). WHSC1 knockdown significantly reduced H3K36me2 modification of the MYC gene promoter in SACC cells and tumorigenesis of SACC cells in vivo (p<0.05). Conclusion: Knockdown of WHSC1 inhibited cell proliferation, induced apoptosis and affected tumorigenesis in SACC. Salivary adenoid cystic carcinoma (SACC) arises from the secretory epithelial cells of the salivary glands (1) and is the most common malignancy of the salivary glands, accounting for about 25-50% of malignant tumors in the major or the minor salivary glands, respectively (2-4). SACC demonstrates unique characteristics that lead to poor prognosis and low overall survival rates (5). Recent molecular pathology findings suggest that genetic translocation and/or overexpression of oncoproteins is important in salivary gland tumorigenesis and diagnosis. Studies have found that the recurrent MYB-NFIB gene fusion is the main genomic hallmark of SACC (6, 7), However, further molecular genetic studies are needed to identify biomarkers as well as therapeutic targets or prognostic factors of ACC. Histone methylation modification is an important process involved in the regulation of oncogenic gene expression and is controlled by histone methyltransferases and demethylases. WHSC1 (also known as NSD2) is a histone methyltransferase that mediates di-methylation of histone 3 lysine 36 (H3K36me2). H3K36 methylation has been found to be associated with transcriptional activation in many cancers 8). Increased expression of WHSC1 was found in many solid tumors, such as multiple myeloma, prostate cancer, breast cancer and head and neck cancer (8-10). In vitro studies indicated that WHSC1 modulates Ras-related 2729 This article is freely accessible online.

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Bcl-2 on the brink of breakthroughs in cancer treatment

Cited by 49 publications

References 16 publications

Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer

Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer

Cell-mediated immune resistance in cancer

Knockdown of Histone Methyltransferase WHSC1 Induces Apoptosis and Inhibits Cell Proliferation and Tumorigenesis in Salivary Adenoid Cystic Carcinoma

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