TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression

Godse, Neal R.; Khan, Nayel; Yochum, Zachary A.; Gomez-Casal, Roberto; Kemp, Carolyn; Shiwarski, Daniel J.; Seethala, Raja S.; Kulich, Scott; Seshadri, Mukund; Burns, Timothy F.; Duvvuri, Umamaheswar

doi:10.1158/1078-0432.ccr-17-1561

Cited by 47 publications

(39 citation statements)

References 24 publications

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“…Recently, it is reported that ONC201 could induce apoptosis by increasing the levels of Bim in myeloma cells [47], AZD9291 (the third generation EGFR inhibitor) could increase the expression of Bim by MEK/ERK-dependent pathway in EGFR-mutant non-small cell lung cancer (NSCLC) cells [48], and the combination of pimasertib (MEK inhibitor) with SAR405838 (MDM2 inhibitor) could induce the expression of Bim in vitro and in vivo in KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas with wild-type TP53 [49]. TMEM16A/ANO1, as a contributor to tumor progression, could inhibit apoptosis via down-regulation of Bim expression [50]. These reports show that Bim may play a critical role in anti-tumor treatment, and may be a new target for clinical cancer therapy strategies.…”

Section: Discussionmentioning

confidence: 99%

The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo

Hua

et al. 2019

J Exp Clin Cancer Res

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Background Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children with poor survival. New treatment approaches are urgently needed to improve treatment efficacy in RMS patients. DMAMCL is a novel agent from Asteraceae family that has been tested in phase I clinical trials in adult glioma in Australia. Methods Five RMS cell lines (RD, RH18, RH28, RH30 and RH41) were used. The in vitro anti-tumor effect of DMAMCL, alone or in combination with VCR or Epirubicin, was studied using MTS assay or IncuCyte-Zoom cell confluency assay, and further validated by xenograft-mouse model in vivo. Changes in caspase-3/7 activity, cell-cycle progression and generation of ROS after DMAMCL treatment were investigated. Bim mRNA expression was measured by RT-qPCR, and protein expressions of Bim and phosphorylated-NF-κB(p65) by Western blotting. Small interfering RNAs (siRNA) of Bim were used to study the role of Bim in DMAMCL-induced cell death. Results In vitro, DMAMCL treatment induced a dose-dependent increase in cell death that could be blocked by pan-caspase-inhibitor-Z-VAD-fmk in five RMS cell lines. The percent of cells in SubG1 phase and activities of caspase-3/7 increased after DMAMCL treatment; The combination of DMAMCL with VCR or Epirubicin significantly increased cell death compared to each reagent alone. In vivo , DMAMCL(75 mg/kg or 100 mg/kg) inhibited tumor growth and prolonged survival of mice bearing xenograft RMS tumors (RD, RH18, RH30, RH41). Compared to treatment with DMAMCL or VCR, a combination of two reagents caused significant inhibition of tumor growth (RD, RH41), even after treatment termination. The expression of Bim increased at protein level after DMAMCL treatment both in vitro and in vivo. The expression of p-NF-κB(p65) had a transient increase and the generation of ROS increased after DMAMCL treatment in vitro. Transfection of Bim siRNA into RMS cells blocked the DMAMCL-induced increase of Bim and partially attenuated the DMAMCL-induced cell death. Conclusion DMAMCL had an anti-tumor growth effect in vitro and in vivo that potentially mediated by Bim, NF-κB pathway and ROS. A combination of DMAMCL with chemotherapeutic drugs significantly increased the treatment efficacy. Our study supports further clinical evaluation of DMAMCL in combination with conventional chemotherapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1107-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo

Hua

et al. 2019

J Exp Clin Cancer Res

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“…Together, these findings suggest that the CCND1 , CTTN and ANO1 genes within the 11q13 amplicon could play a significant role in HPV-negative tumors but not in HPV-positive tumors. Given that 11q13 amplification has been associated with poor prognosis in HNSCC patients, and, in particular, these three genes have been involved in tumor progression and resistance to radio-, chemotherapy [11,22,23,24,25,26], and EGFR-targeted therapies [27], the herein found distinctive molecular alterations presumably could contribute to the clinical and biological differences between these two different HNSCC subtypes and explain the better prognosis and response to radiotherapy and chemotherapy associated to HPV-positive tumors. In fact, we proved the impact of these molecular alterations on patient survival.…”

Section: Discussionmentioning

confidence: 99%

Distinctive Expression and Amplification of Genes at 11q13 in Relation to HPV Status with Impact on Survival in Head and Neck Cancer Patients

Hermida-Prado

Menéndez

Albornoz-Afanasiev

et al. 2018

JCM

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Clear differences have been established between head and neck squamous cell carcinomas (HNSCC) depending on human papillomavirus (HPV) infection status. This study specifically investigated the status of the CTTN, CCND1 and ANO1 genes mapping at the 11q13 amplicon in relation to the HPV status in HNSCC patients. CTTN, CCND1 and ANO1 protein expression and gene amplification were respectively analyzed by immunohistochemistry and real-time PCR in a homogeneous cohort of 392 surgically treated HNSCC patients. The results were further confirmed using an independent cohort of 279 HNSCC patients from The Cancer Genome Atlas (TCGA). The impact on patient survival was also evaluated. CTTN, CCND1 and ANO1 gene amplification and protein expression were frequent in HPV-negative tumors, while absent or rare in HPV-positive tumors. Using an independent validation cohort of 279 HNSCC patients, we consistently found that these three genes were frequently co-amplified (28%) and overexpressed (39–46%) in HPV-negative tumors, whereas almost absent in HPV-positive tumors. Remarkably, these alterations (in particular CTTN and ANO1 overexpression) were associated with poor prognosis. Taken together, the distinctive expression and amplification of these genes could cooperatively contribute to the differences in prognosis and clinical outcome between HPV-positive and HPV-negative tumors. These findings could serve as the basis to design more personalized therapeutic strategies for HNSCC patients.

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“…Ion channels in general, and Ca 2+ -activated chloride channels in particular, are known to be involved in the regulation of cell proliferation, cell migration and metastasis and are believed to be important emerging drug targets in cancer (2,3). A calcium-dependent chloride channel, TMEM16A, has also been proposed to contribute to tumor growth and invasion in lung cancer, prostate cancer and head and neck squamous cell carcinomas (26)(27)(28)(29). Since CLCA1 has been demonstrated to be a direct modulator of TMEM16A, its role in tumorigenesis is increasingly recognized.…”

Section: Role In Cancermentioning

confidence: 99%

The Emerging Role of Calcium-activated Chloride Channel Regulator 1 in Cancer

Ansari

Bauden

et al. 2019

Anticancer Res

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Calcium-activated chloride channel regulator 1 (CLCA1) belongs to a group of secreted self-cleaving proteins, which activate calcium-dependent chloride channels. CLCA1 has been shown to participate in the pathogenesis of inflammatory airway diseases such as asthma. Recently, additional functions of CLCA1 have been unveiled, including its metalloprotease property and involvement in mucus homeostasis and immune modulation. Emerging evidence suggests that CLCA1 may also be involved in the pathophysiology of colorectal, pancreatic and ovarian cancer. There is growing interest in utilizing CLCA1 as a diagnostic, prognostic and predictive biomarker, as well as a potential therapeutic target. In this review, the functional role of CLCA1, with a particular focus on cancer, is described. Calcium-activated chloride channel regulators (CLCAs), also called chloride channel accessory proteins, are a family of secreted self-cleaving proteins, which activate calciumdependent chloride channels. CLCAs have been implicated in the regulation of cell proliferation, cell migration and metastasis and are believed to be emerging therapeutic targets in cancer (1-3). The human genome encodes three functional CLCAs, including CLCA1, CLCA2, and CLCA4. CLCA3 is a truncated pseudogene and does not encode a protein (4). Among the CLCAs, CLCA1 possesses unique characteristics, which attribute to this protein a role in mucus homeostasis. CLCA1 is well studied due to its link to development of inflammatory airway disease (5). However, recent data indicate that CLCA1 may also be involved in neoplasia (6, 7). Consequently, CLCA1 has been suggested as a novel biomarker and a potential therapeutic target for various malignancies. Here, a comprehensive summary of the molecular structure, function and regulation of CLCA1 in cancer is provided.

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TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression

Cited by 47 publications

References 24 publications

The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo

The anti-tumor growth effect of a novel agent DMAMCL in rhabdomyosarcoma in vitro and in vivo

Distinctive Expression and Amplification of Genes at 11q13 in Relation to HPV Status with Impact on Survival in Head and Neck Cancer Patients

The Emerging Role of Calcium-activated Chloride Channel Regulator 1 in Cancer

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