BMP4-Smad Signaling Pathway Mediates Adriamycin-induced Premature Senescence in Lung Cancer Cells

Su, Dongmei; Zhu, Shan; Han, Xiaoyan; Feng, Yunpeng; Huang, Hui; Ren, Guoling; Pan, Lina; Zhang, Yu; Lü, Jun; Huang, Baiqu

doi:10.1074/jbc.m807930200

Cited by 49 publications

(43 citation statements)

References 39 publications

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“…Now the evaluation of the different BMP signaling pathways revealed that the canonical SMAD1/5/8 pathway is indeed activated in these breast cancer cell lines after BMP4 treatment. Most of the previous studies, for example in pancreatic, lung, and colorectal cancer, also show that BMP4 typically signals through the SMAD pathway [21,34,39,40,50,54]. None of the studied cell lines showed activation of MAP kinases ERK1/2 or p38 in response to BMP4 even though such responses have been reported in human mammary epithelial cells [55] and in pancreatic cancer cells [40].…”

Section: Discussionmentioning

confidence: 72%

Parallel inhibition of cell growth and induction of cell migration and invasion in breast cancer cells by bone morphogenetic protein 4

Ketolainen

Alarmo

Tuominen³

et al. 2010

Breast Cancer Res Treat

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Bone morphogenetic proteins (BMP) are extracellular signaling molecules that belong to the transforming growth factor β (TGFβ) superfamily. Bone morphogenetic proteins have diverse roles during development where they regulate proliferation, differentiation, and apoptosis in many different cell types by modulating the transcription of specific target genes. BMPs have also been implicated in both promotion and inhibition of cancer progression. We have recently shown that BMP4 is commonly expressed in breast cancer but its functional significance has not been previously explored. Our data demonstrate that in all nine breast cancer cell lines studied, BMP4 treatment leads to a dramatic growth suppression as a result of the induction of G1 arrest of the cell cycle. At the same time, BMP4 stimulates cell migration and invasion in a subset of these breast cancer cell lines. The BMP4-induced phenotypic changes were mediated through the activation of the canonical SMAD signaling pathway whereas no activation of MAP-kinases ERK1/2 or p38 was detected. Our results thus implicate that BMP4 is an important regulator of key phenotypic characteristics of cancer cells, cell growth, cell migration, and invasion, and that, similar to TGFβ, it possesses both tumor suppressive and oncogenic properties in breast cancer.

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Section: Discussionmentioning

confidence: 72%

Parallel inhibition of cell growth and induction of cell migration and invasion in breast cancer cells by bone morphogenetic protein 4

Ketolainen

Alarmo

Tuominen³

et al. 2010

Breast Cancer Res Treat

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“…While the role of BMP4 in aging is less understood, some reports have indicated that BMP4 is an important mediator of atrophic age-related macular degeneration because it mediates oxidative stress-induced retinal pigment epithelium senescence in vitro via the SMAD and p38 pathways ). In addition, overexpression of BMP4 was able to induce premature senescence in lung cancer cells (Su et al 2009). The role of Biogerontology (2011) 12:293-308 301 BMP4 in epigenetic regulation and in IUGR is also not well understood, but a recent article by Murohashi et al (2010) showed that trophoblast cells produce BMP4 by means of CDX2 to promote the proper growth of early mouse embryos.…”

Section: A Common Regulatory Pathway For Development and Aging In H mentioning

confidence: 98%

The developmental aging and origins of health and disease hypotheses explained by different protein networks

2011

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One theory that attempts to explain how and why an organism ages is the developmental hypothesis of aging (DevAge), which describes how developmental programming leads to aging in adults. Interestingly, the developmental origins of health and disease hypothesis (DOHaD) asserts that some aging-associated diseases that occur in adults are closely related to development and to conditions in the intrauterine environment. Thus, both aging and aging-associated diseases can be viewed, at least in part, as the result of a developmental program that is activated early in embryogenesis and persists throughout the lifespan of the organism. We would expect this developmental program to be regulated by a set of interacting protein networks that connect environmental and molecular signals. However, the connection between aging and development is not clear. Thus, a systems biology approach that incorporates different "omic" databases for two mammalian models, Homo sapiens and Mus musculus, was used to evaluate how development and aging are interconnected. Interestingly, three major, evolutionarily conserved processes, namely the immune system, epigenetics, and aerobic metabolism, appear to regulate aging and development in both H. sapiens and M. musculus. Considering that these three processes are essential to embryogenesis, the protein networks within these processes are subjected to strong selective pressure to eliminate gross developmental abnormalities in early embryogenesis. This selective pressure becomes more relaxed in the adult organism, permitting the onset of aging-associated diseases and inflammation-related aging; this concept echoes the antagonistic pleiotropy hypothesis of aging.

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“…We and others have demonstrated that treatment of tumor cells with Adriamycin preferentially induces senescence rather than apoptotic cell death (Chang et al, 1999;Elmore et al, 2002;Su et al, 2009). In addition, previous studies in thyroid cancer and hepatoma cells have demonstrated that Adriamycin can induce autophagy (Lin et al, 2009;Qian and Yang, 2009).…”

Section: Discussionmentioning

confidence: 99%

The Autophagy-Senescence Connection in Chemotherapy: Must Tumor Cells (Self) Eat Before They Sleep?

Goehe

Di²,

Sharma³

et al. 2012

J Pharmacol Exp Ther

121

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Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma cells to clinically relevant concentrations of doxorubicin (Adriamycin; Farmitalia Research Laboratories, Milan, Italy) or camptothecin results in both autophagy and senescence. To determine whether autophagy is required for chemotherapyinduced senescence, reactive oxygen generation induced by Adriamycin was suppressed by N-acetyl cysteine and glutathione, and the induction of ataxia telangiectasia mutated, p53, and p21 was modulated pharmacologically and/or genetically. In all cases, autophagy and senescence were collaterally suppressed. The close association between autophagy and senescence indicated by these experiments reflects their collateral regulation via common signaling pathways. The potential relationship between autophagy and senescence was further examined through pharmacologic inhibition of autophagy with chloroquine and 3-methyl-adenine and genetic ablation of the autophagy-related genes ATG5 and ATG7. However, inhibition of autophagy by pharmacological and genetic approaches could not entirely abrogate the senescence response, which was only reduced and/or delayed. Taken together, our findings suggest that autophagy and senescence tend to occur in parallel, and furthermore that autophagy accelerates the development of the senescent phenotype. However, these responses are not inexorably linked or interdependent, as senescence can occur when autophagy is abrogated.

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BMP4-Smad Signaling Pathway Mediates Adriamycin-induced Premature Senescence in Lung Cancer Cells

Cited by 49 publications

References 39 publications

Parallel inhibition of cell growth and induction of cell migration and invasion in breast cancer cells by bone morphogenetic protein 4

Parallel inhibition of cell growth and induction of cell migration and invasion in breast cancer cells by bone morphogenetic protein 4

The developmental aging and origins of health and disease hypotheses explained by different protein networks

The Autophagy-Senescence Connection in Chemotherapy: Must Tumor Cells (Self) Eat Before They Sleep?

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