Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth

Cassar, Lucy; Li, He; Pinto, Alexander R.; Nicholls, Craig; Bayne, Sharyn Leanne; Liu, Junping

doi:10.1158/0008-5472.can-08-1323

Cited by 35 publications

(45 citation statements)

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“…In keeping with this, data from the MTT cell proliferation assay showed no differences in cell viability and proliferation between control and A549 cells. BMP7 has been indicated to act as a mediator/regulator of cell survival and apoptosis in several tumour cell lines (3,(6)(7)(8)13,25,26,27), including prostate cancer cells, colon cancer cells, breast cancer cells and melanoma cells and renal cancer cells. In the present study, our results from the apoptosis assay showed that BMP7 offers no significant protection against apoptosis in the tumour cells transfected with BMP7 in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Distant metastasis is an important cause for the poor prognosis. Of the factors related to metastasis, bone morphogenetic proteins (BMPs) have been recently shown to regulate the aggressiveness of cancer cells (1)(2)(3)(4)(5)(6)(7). BMPs are multifunctional signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily, which play important roles in multiple cellular processes such as cell growth, differentiation, migration and apoptosis in various types of cancer (8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

et al. 2012

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Abstract. The aim of this study was to investigate the expression of bone morphogenetic protein 7 (BMP7), in human pulmonary cancer tissues/cells and to evaluate the cellular impact of bone morphogenetic proteins on pulmonary cancer cells. BMP7 expression was determined in human lung cancer cell lines. The invasiveness and growth of cells transfected with BMP7, in vitro, were evaluated using the in vitro invasion assay and in vitro tumour models. Cellular migration was analysed using wounding assays. BMP7-positive tumours correlated with the absence of bone metastasis (P=0.040). In this analysis, we identified that 4 of 4 small cell lung cancer (SCLC) tissue specimens had no BMP7 expression, which illustrated that BMP7 may have no role in SCLC. BMP7 expression was not correlated with the overall survival time in lung cancer patients. Downregulation of BMP7 expression significantly inhibited the invasiveness of SPC-A1 cells (P<0.001) and forced-expression of BMP7 dramatically increased the motility of A549 cells. Overexpression of BMP7 in A549 cells and its knockdown in SPC-A1 cells did not significantly alter proliferation compared with the control cells (P>0.5 respectively). In conclusion, we have demonstrated that BMP7 has an important role in controlling lung cancer cell motility and invasiveness, without affecting the growth process, cell proliferation and cell apoptosis. A higher BMP7 expression may be an indicator for bone metastasis. The therapeutic role of BMP7 warrants further investigation. IntroductionLung cancer is one of the most fatal tumours worldwide. Distant metastasis is an important cause for the poor prognosis. Of the factors related to metastasis, bone morphogenetic proteins (BMPs) have been recently shown to regulate the aggressiveness of cancer cells (1-7). BMPs are multifunctional signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily, which play important roles in multiple cellular processes such as cell growth, differentiation, migration and apoptosis in various types of cancer (8-12). The Smad-dependent signaling pathway has been proven to be the canonical pathway for BMP function (13). In lung cancer, expression of the BMP family members has also been reported (1,14). For example, BMP2 protein could stimulate growth, migration and invasion of lung cancer cells, and is overexpressed in virtually all types of lung cancers, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Silencing of BMP3b expression during NSCLC development has been reported and the BMP3b promoter has been found to be methylated. Activation of the BMP4 signaling pathway negatively regulates the growth, and induces senescence of A549 lung adenocarcinoma cells. Thus, there may be a contrasting response to any given BMP, depending on the tumour and cell type. Despite the discordant results defining the specific effects of BMP7 in various types of cancer, published data underscore the important role that BMP7 plays in tumour development and metastasis. The expre...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

et al. 2012

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“…Telomere repeat amplification protocol assays and telomere length analysis were performed as previously described (44) with minor modifications (45,46).…”

Section: Methodsmentioning

confidence: 99%

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

Nicholls

Pinto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Oxidative stress regulates telomere homeostasis and cellular aging by unclear mechanisms. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key mediator of many oxidative stress responses, involving GAPDH nuclear translocation and induction of cell death. We report here that GAPDH interacts with the telomerase RNA component (TERC), inhibits telomerase activity, and induces telomere shortening and breast cancer cell senescence. The Rossmann fold containing NAD + binding region on GAPDH is responsible for the interaction with TERC, whereas a lysine residue in the GAPDH catalytic domain is required for inhibiting telomerase activity and disrupting telomere maintenance. Furthermore, the GAPDH substrate glyceraldehyde-3-phosphate (G3P) and the nitric oxide donor S-nitrosoglutathione (GSNO) both negatively regulate GAPDH inhibition of telomerase activity. Thus, we demonstrate that GAPDH is regulated to target the telomerase complex, resulting in an arrest of telomere maintenance and cancer cell proliferation. and apoptosis. Although production of daughter cells costs energy, it remains largely elusive how energy metabolism regulates normal cell aging and lifespan. Considerable evidence suggests that metabolic waste causes premature senescence and apoptosis, shortening cellular lifespan. Accumulation of reactive oxygen species (ROS) damages cellular enzymes, organelle membranes, and chromosomal DNA including telomeres (the ends of chromosomes) (1, 2). Whereas enzymes that reduce the production of metabolic hazards may operate to extend cellular lifespan, recent studies demonstrate that the energy producing enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) that limits ROS production undergoes structural modifications and travel into the nucleus (3-7) to interact with telomeres directly and to potentially alleviate stress-induced cell aging (8, 9).Human telomeres are composed of arrays of a few thousand tandem DNA repeats of TTAGGG and various binding proteins. Telomeres undergo progressive shortening as somatic cells divide, due to the inability of cells to replicate the extreme ends of chromosomes. When telomeres are critically short, cells exit the cell cycle and undergo cell senescence (10-13). As a measure to maintain telomeres for continuous renewal of germ lines, development of embryonic stem cells, clonal expansion of lymphocytes, and immortalization of neoplastic cells, telomerase is activated to synthesize and maintain telomeres by reverse transcription (10-13).Telomerase is a large ribonucleoprotein complex containing the catalytic subunit telomerase reverse transcriptase (TERT) and an RNA template (reviewed in refs. 13 and 14). Human telomerase reverse transcriptase (hTERT) comprises 1,132 amino acid residues and human telomerase RNA (hTERC) is composed of 451 nucleotides (15-18). Reconstitution of telomerase activity in telomerase-negative cells can be achieved by expression of hTERT, demonstrating that hTERT is the rate-limiting component of the enzyme complex (19,20).GAPDH has long been recognize...

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“…Gremlin 1 is also reported to be expressed in cervical cancer compared to normal tissues of the cervix (37). A few studies have investigated the significance of BMPs in cervical cancer (38)(39)(40), however, there are no studies on the clinicopathological significance of Gremlin 1 in cervical cancer nor on the function of Gremlin 1 in CSC-like cells of cervical cancer.…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance

et al. 2015

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Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth

Cited by 35 publications

References 50 publications

Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

Clinical significance of Gremlin 1 in cervical cancer and its effects on cancer stem cell maintenance

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