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9. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1

Author

Furuta, Eiji, Pai, Sudha K, Zhan, Rui, Bandyopadhyay, Sucharita, Watabe, Misako, Mo, Yin-Yuan, Hirota, Shigeru, Hosobe, Sadahiro, Tsukada, Taisei, Miura, Kunio, Kamada, Shuichi, Saito, Ken, Iiizumi, Megumi, Liu, Wen, Ericsson, Johan, Watabe, Kounosuke, Furuta, Eiji, Pai, Sudha K, Zhan, Rui, Bandyopadhyay, Sucharita, Watabe, Misako, Mo, Yin-Yuan, Hirota, Shigeru, Hosobe, Sadahiro, Tsukada, Taisei, Miura, Kunio, Kamada, Shuichi, Saito, Ken, Iiizumi, Megumi, Liu, Wen, Ericsson, Johan, and Watabe, Kounosuke

Abstract

The fatty acid synthase (FAS) gene is significantly up-regulated in various types of cancers, and blocking the FAS expression results in apoptosis of tumor cells. Therefore, FAS is considered to be an attractive target for anticancer therapy. However, the molecular mechanism by which the FAS gene is up-regulated in tumor cells is poorly understood. We found that FAS was significantly up-regulated by hypoxia, which was also accompanied by reactive oxygen species (ROS) generation in human breast cancer cell lines. The FAS expression was also activated by H(2)O(2), whereas N-acetyl-L-cystein, a ROS inhibitor, suppressed the expression. We also found that the hypoxia significantly up-regulated sterol regulatory-element binding protein (SREBP)-1, the major transcriptional regulator of the FAS gene, via phosphorylation of Akt followed by activation of hypoxia-inducible factor 1 (HIF1). Moreover, our results of reporter assay and chromatin immunoprecipitation analysis indicate that SREBP-1 strongly bound to the SREBP binding site/E-box sequence on the FAS promoter under hypoxia. In our xenograft mouse model, FAS was strongly expressed in the hypoxic regions of the tumor. In addition, our results of immunohistochemical analysis for human breast tumor specimens indicate that the expressions of both FAS and SREBP-1 were colocalized with hypoxic regions in the tumors. Furthermore, we found that hypoxia-induced chemoresistance to cyclophosphamide was partially blocked by a combination of FAS inhibitor and cyclophosphamide. Taken together, our results indicate that FAS gene is up-regulated by hypoxia via activation of the Akt and HIF1 followed by the induction of the SREBP-1 gene, and that hypoxia-induced chemoresistance is partly due to the up-regulation of FAS.

Published
2008
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11. Abstract 3865: HAS2 promotes tumor progression by stimulating interaction of cancer stem-like cells with tumor associated macrophage and stromal cells through a paracrine loop of growth factors in the bone.

Author

Sharma, Sambad, primary, Okuda, Hiroshi, additional, Xing, Fei, additional, Kobayashi, Aya, additional, Watabe, Misako, additional, Pandey, Puspa R., additional, Pai, Sudha K., additional, Liu, Wen, additional, Fukuda, Koji, additional, Iiizumi, Megumi, additional, and Watabe, Kounosuke, additional

Published
2013
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12. miR-7 Suppresses Brain Metastasis of Breast Cancer Stem-Like Cells By Modulating KLF4

Author

Okuda, Hiroshi, primary, Xing, Fei, additional, Pandey, Puspa R., additional, Sharma, Sambad, additional, Watabe, Misako, additional, Pai, Sudha K., additional, Mo, Yin-Yuan, additional, Iiizumi-Gairani, Megumi, additional, Hirota, Shigeru, additional, Liu, Yin, additional, Wu, Kerui, additional, Pochampally, Radhika, additional, and Watabe, Kounosuke, additional

Published
2013
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18. Abstract 3419: N-myc downstream regulated gene 1, NDRG1, modulates Wnt-β-catenin signaling and pleiotropically suppresses metastasis

Author

Liu, Wen, primary, Xing, Fei, additional, Iiizumi-Gairani, Megumi, additional, Okuda, Hiroshi, additional, Watabe, Misako, additional, Pai, Sudha K., additional, Pandey, Puspa R., additional, Hirota, Shigeru, additional, Kobayashi, Aya, additional, Fukuda, Koji, additional, Li, Yi, additional, and Watabe, Kounosuke, additional

Published
2012
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20. Hyaluronan Synthase HAS2 Promotes Tumor Progression in Bone by Stimulating the Interaction of Breast Cancer Stem–Like Cells with Macrophages and Stromal Cells

Author

Okuda, Hiroshi, primary, Kobayashi, Aya, additional, Xia, Bo, additional, Watabe, Misako, additional, Pai, Sudha K., additional, Hirota, Shigeru, additional, Xing, Fei, additional, Liu, Wen, additional, Pandey, Puspa R., additional, Fukuda, Koji, additional, Modur, Vishnu, additional, Ghosh, Arnab, additional, Wilber, Andrew, additional, and Watabe, Kounosuke, additional

Published
2012
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22. Abstract 1028: Hypoxia induces Notch signaling and promotes breast cancer metastasis by stimulating growth and self renewal of cancer stem-like cells

Author

Xing, Fei, primary, Okuda, Hiroshi, additional, Watabe, Misako, additional, Kobayashi, Aya, additional, Pai, Sudha K., additional, Liu, Wen, additional, Pandey, Puspa R., additional, Fukuda, Koji, additional, Hirota, Shigeru, additional, Sugai, Tamotsu, additional, Wakabayashi, Go, additional, Koeda, Keisuke, additional, Kashiwaba, Masahiro, additional, Suzuki, Kazuyuki, additional, Chiba, Toshimi, additional, Endo, Masaki, additional, and Watabe, Kounosuke, additional

Published
2011
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23. Abstract 3409: Hyaluronan synthase 2 promotes tumor progression by stimulating interaction of cancer stem-like cells with tumor associated macrophage and stromal cells in the bone

Author

Okuda, Hiroshi, primary, Kobayashi, Aya, additional, Watabe, Misako, additional, Pai, Sudha K., additional, Liu, Wen, additional, Xing, Fei, additional, Pandey, Puspa R., additional, Fukuda, Koji, additional, Iiizumi, Megumi, additional, and Watabe, Kounosuke, additional

Published
2011
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26. Abstract 979: Upregulation of lipogenic genes, SREBP-1, ACLY, ACC-1 and FAS, confer proliferation and survival advantages to cancer stem-like cells in ductal carcinoma in situ

Author

Tomoaki Fujioka, Puspa R. Pandey, Tamotsu Sugai, Watabe Misako, Yin-Yuan Mo, Deliang Cao, Aya Kobayashi, Andrew Wilber, Hiroshi Okuda, Go Wakabayashi, Fei Xing, Masaki Endo, Keisuke Koeda, Wen Liu, Kazuyuki Suzuki, Kounosuke Watabe, Toshimi Chiba, Masahiro Kashiwaba, Sudha K. Pai, Koji Fukuda, Shigeru Hirota, and Susumu Tanji

Subjects
Cancer Research, medicine.medical_specialty, biology, CD24, CD44, Cancer, Resveratrol, medicine.disease, medicine.disease_cause, body regions, chemistry.chemical_compound, Endocrinology, Oncology, Downregulation and upregulation, chemistry, Apoptosis, Internal medicine, Lipogenesis, medicine, Cancer research, biology.protein, skin and connective tissue diseases, Carcinogenesis, neoplasms
Abstract

Elevated level of lipogenic enzymes and overall lipogenesis have been reported in a wide variety of cancers, and blocking the lipogenic pathway by chemical inhibitors or RNA interference causes tumor cell death by apoptosis. In this study, we investigated the role of lipogenesis in cancer stem-like cells (CSCs) in ductal carcinoma in situ (DCIS) which is considered as an early stage of breast tumorigenesis. CSCs were isolated using cell surface markers (CD24−/CD44+/ESA+) from the MCF10DCIS. Com (DCIS.com) cell line and transplanted into the mammary fat pad of nude mice. The results of our limiting dilution analysis indicate that CSCs had a significantly higher ability of initiating DCIS in the animals. We then examined the expression profile of various lipogenic genes using an expression microarray and found that CSCs from DCIS.com showed significantly higher level of ACLY, ACC-1 and FAS than the normal non-tumorigenic stem-like cells. The result was also confirmed by qRT-PCR and Western blot. We also examined the expression of these genes in clinical specimens of DCIS by immunohistochemistry and found that these genes are indeed significantly upregulated. Furthermore, we found SREBP1, the master regulator of lipogenic genes, was also significantly upregulated in DCIS clinical specimens as well as in DCIS.com cells and inhibition of SREBP1 significantly downregulated the expression of ACLY, ACC-1 and FAS. These results suggest that the lipogenic enzymes play critical roles in initiation and maintenance of DCIS. We then examined the effects of Resveratrol, a natural polyphenol, on CSCs isolated from DCIS.com. We found that Resveratrol reduced the total lipid content of DCIS CSCs by inhibiting lipogenic genes and induced a series of pro-apoptotic genes causing the death of DCIS CSCs. Resveratrol also hindered the stemness of the DCIS CSCs by inhibiting its mammosphere forming ability. When DCIS CSCs was transplanted into mammary fat pad of nude mice followed by treatment with Resveratrol, we observed that Resveratrol indeed significantly suppressed the formation of DCIS by downregulating lipogenic genes and by upregulating pro-apoptotic genes, DAPK2 and BNIP3. Collectively, our results indicate that lipogenic genes ACLY, ACC-1, FAS and SREBP1 are significantly up regulated in DCIS CSCs at an early stage of breast tumorigenesis and they confer proliferative and anti-apoptotic capacity to CSCs. Anti-growth effect of Resveratrol on DCIS CSCs also provides us with a strong rationale to use this agent for chemo-prevention against DCIS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 979. doi:10.1158/1538-7445.AM2011-979

Published
2011
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27. RhoC Promotes Metastasis via Activation of the Pyk2 Pathway in Prostate Cancer

Author

Iiizumi, Megumi, primary, Bandyopadhyay, Sucharita, additional, Pai, Sudha K., additional, Watabe, Misako, additional, Hirota, Shigeru, additional, Hosobe, Sadahiro, additional, Tsukada, Taisei, additional, Miura, Kunio, additional, Saito, Ken, additional, Furuta, Eiji, additional, Liu, Wen, additional, Xing, Fei, additional, Okuda, Hiroshi, additional, Kobayashi, Aya, additional, and Watabe, Kounosuke, additional

Published
2008
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28. Fatty Acid Synthase Gene Is Up-regulated by Hypoxia via Activation of Akt and Sterol Regulatory Element Binding Protein-1

Author

Furuta, Eiji, primary, Pai, Sudha K., additional, Zhan, Rui, additional, Bandyopadhyay, Sucharita, additional, Watabe, Misako, additional, Mo, Yin-Yuan, additional, Hirota, Shigeru, additional, Hosobe, Sadahiro, additional, Tsukada, Taisei, additional, Miura, Kunio, additional, Kamada, Shuichi, additional, Saito, Ken, additional, Iiizumi, Megumi, additional, Liu, Wen, additional, Ericsson, Johan, additional, and Watabe, Kounosuke, additional

Published
2008
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29. The Tumor Metastasis Suppressor Gene Drg-1 Down-regulates the Expression of Activating Transcription Factor 3 in Prostate Cancer

Author

Bandyopadhyay, Sucharita, primary, Wang, Ying, additional, Zhan, Rui, additional, Pai, Sudha K., additional, Watabe, Misako, additional, Iiizumi, Megumi, additional, Furuta, Eiji, additional, Mohinta, Sonia, additional, Liu, Wen, additional, Hirota, Shigeru, additional, Hosobe, Sadahiro, additional, Tsukada, Taisei, additional, Miura, Kunio, additional, Takano, Yukio, additional, Saito, Ken, additional, Commes, Therese, additional, Piquemal, David, additional, Hai, Tsonwin, additional, and Watabe, Kounosuke, additional

Published
2006
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30. Mechanism of Apoptosis Induced by the Inhibition of Fatty Acid Synthase in Breast Cancer Cells

Author

Bandyopadhyay, Sucharita, primary, Zhan, Rui, additional, Wang, Ying, additional, Pai, Sudha K., additional, Hirota, Shigeru, additional, Hosobe, Sadahiro, additional, Takano, Yukio, additional, Saito, Ken, additional, Furuta, Eiji, additional, Iiizumi, Megumi, additional, Mohinta, Sonia, additional, Watabe, Misako, additional, Chalfant, Charles, additional, and Watabe, Kounosuke, additional

Published
2006
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31. PTEN Up-Regulates the Tumor Metastasis Suppressor GeneDrg-1in Prostate and Breast Cancer

Author

Bandyopadhyay, Sucharita, primary, Pai, Sudha K., additional, Hirota, Shigeru, additional, Hosobe, Sadahiro, additional, Tsukada, Taisei, additional, Miura, Kunio, additional, Takano, Yukio, additional, Saito, Ken, additional, Commes, Therese, additional, Piquemal, David, additional, Watabe, Misako, additional, Gross, Steven, additional, Wang, Ying, additional, Huggenvik, Jodi, additional, and Watabe, Kounosuke, additional

Published
2004
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32. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone

Author

Kobayashi, Aya, Okuda, Hiroshi, Xing, Fei, Pandey, Puspa R., Watabe, Misako, Hirota, Shigeru, Pai, Sudha K., Liu, Wen, Fukuda, Koji, Chambers, Christopher, Wilber, Andrew, and Watabe, Kounosuke

Abstract

Metastatic disease is the major cause of cancer deaths, and recurrent tumors at distant organs are a critical issue. However, how metastatic tumor cells become dormant and how and why tumors recur in target organs are not well understood. In this study, we demonstrate that BMP7 (bone morphogenetic protein 7) secreted from bone stromal cells induces senescence in prostate cancer stem-like cells (CSCs) by activating p38 mitogen-activated protein kinase and increasing expression of the cell cycle inhibitor, p21, and the metastasis suppressor gene, NDRG1 (N-myc downstream-regulated gene 1). This effect of BMP7 depended on BMPR2 (BMP receptor 2), and BMPR2 expression inversely correlated with recurrence and bone metastasis in prostate cancer patients. Importantly, this BMP7-induced senescence in CSCs was reversible upon withdrawal of BMP7. Furthermore, treatment of mice with BMP7 significantly suppressed the growth of CSCs in bone, whereas the withdrawal of BMP7 restarted growth of these cells. These results suggest that the BMP7–BMPR2–p38–NDRG1 axis plays a critical role in dormancy and recurrence of prostate CSCs in bone and suggest a potential therapeutic utility of BMP7 for recurrent metastatic disease.

Published
2011
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33. KAI1 Gene Is Engaged in NDRG1 Gene-mediated Metastasis Suppression through the ATF3-NFκB Complex in Human Prostate Cancer.

Author

Wen Liu, Iiizumi-Gairani, Megumi, Okuda, Hiroshi, Kobayashi, Aya, Watabe, Misako, Pai, Sudha K., Pandey, Puspa R., Fei Xing, Fukuda, Koji, Modur, Vishnu, Hirota, Shigeru, Suzuki, Kazuyuki, Chiba, Toshimi, Endo, Masaki, Sugai, Tamotsu, and Watabe, Kounosuke

Subjects
*TUMOR suppressor proteins, *CANCER cells, *METASTASIS, *TRANSCRIPTION factors, *GENE expression, *PROSTATE cancer
Abstract

NDRG1 and KAI1 belong to metastasis suppressor genes, which impede the dissemination of tumor cells from primary tumors to distant organs. Previously, we identified the metastasis promoting transcription factor, ATF3, as a downstream tar- get of NDRG1. Further analysis revealed that the KAI1 promoter contained a consensus binding motif of ATF3, suggesting a pos- sibility that NDRG1 suppresses metastasis through inhibition of ATF3 expression followed by activation of the KAI1 gene. In this report, we found that ectopic expression of NDRG1 was able to augment endogenous KAI1 gene expression in prostate cancer cell lines, whereas silencing NDRG1 was accompanied with significant decrease in KAI1 expression in vitro and in vivo. In addition, our results of ChIP analysis indicate that ATF3 indeed bound to the promoter of the KAI1 gene. Importantly, our promoter-based analysis revealed that ATF3 modulated KAI1 transcription through cooperation with other endogenous transcription factor as co-activator (ATF3-JunB) or co-repressor (ATF3-NFκB). Moreover, loss of KAI1 expression significantly abrogated NDRG1-mediated metastatic suppression in vitro as well as in a spontaneous metastasis animal model, indicating that KAI1 is a functional downstream target of the NDRG1 pathway. Our result of immunohistochemical analysis showed that loss of NDRG1 and KAI1 occurs in parallel as prostate cancer progresses. We also found that a combined expression status of these two genes serves as a strong independent prognostic marker to predict metastasis-free survival of prostate cancer patients. Taken together, our result revealed a novel regulatory network of two metastasis suppressor genes, NDRG1 and KAI1, which together concerted metastasis-suppressive activities through an intrinsic transcriptional cascade. [ABSTRACT FROM AUTHOR]

Published
2011
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34. PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer.

Author

Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Commes T, Piquemal D, Watabe M, Gross S, Wang Y, Huggenvik J, and Watabe K

Subjects
Breast Neoplasms mortality, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Male, PTEN Phosphohydrolase, Prostatic Neoplasms mortality, Survival Rate, Up-Regulation, Breast Neoplasms genetics, Cell Cycle Proteins genetics, Genes, Tumor Suppressor, Phosphoric Monoester Hydrolases physiology, Prostatic Neoplasms genetics, Tumor Suppressor Proteins physiology
Abstract

PTEN (phosphatase and tensin homologue deleted on chromosome 10) has been shown to be inactivated in a wide variety of cancers, and the role of this gene as a tumor suppressor has been well established. On the other hand, results of recent animal studies as well as clinical evidence indicate that PTEN is also involved in tumor metastasis suppression. Although PTEN is known to play a key role in controlling cell growth and apoptosis, how PTEN exerts the metastasis suppressor function remains largely unknown. Recently, a microarray analysis identified the Drg-1 gene (differentiation related gene 1) as one of the potential targets of PTEN. The Drg-1 gene has been shown to suppress tumor metastasis in animal models of prostate and colon cancer, and the expression of this gene is significantly reduced with advancement of prostate and breast cancers in clinical setting. In this study, we explored the possibility that PTEN controls tumor metastasis by regulating the expression of the Drg-1 gene. Our results indicate that overexpression of PTEN significantly augments the endogenous expression of Drg-1 protein, whereas inhibition of PTEN by small interfering RNA decreases Drg-1 in a dose- and time-dependent manner. We also found that the control of the Drg-1 gene by PTEN seems to be at the transcriptional level, and that a phospho-Akt inhibitor restores the Drg-1 expression, indicating that PTEN controls Drg-1 by an Akt-dependent pathway. Consistent with these results, our immunohistochemical analysis revealed that PTEN expression correlates significantly with Drg-1 in both prostate and breast cancer cases. Furthermore, combination of the two markers, PTEN and Drg-1, emerged as a significantly better predictor of prostate and breast cancer patient survival than either marker alone.

Published
2004
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35. The Drg-1 gene suppresses tumor metastasis in prostate cancer.

Author

Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, Saito K, Commes T, Hayashi S, Watabe M, and Watabe K

Subjects
Aged, Aged, 80 and over, Animals, Cell Cycle Proteins biosynthesis, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Lung Neoplasms genetics, Lung Neoplasms secondary, Male, Mice, Mice, SCID, Middle Aged, Neoplasm Invasiveness, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Transfection, Cell Cycle Proteins genetics, Genes, Tumor Suppressor, Prostatic Neoplasms genetics
Abstract

Drg-1 was previously identified (N. van Belzen et al., Lab. Investig., 77: 85-92, 1997) as a gene that was up-regulated by the induction of differentiation in a colon carcinoma cell line in vitro. Subsequently, this gene was found to be regulated by several factors including hypoxia, androgen, p53, and N-myc. Recently, Drg-1 has also been shown to be involved in tumor progression in animals, although the clinical significance of its involvement remains to be investigated. To clarify the functional role of Drg-1 in prostate cancer, we examined a clinical archive of cancer specimens for the expression of Drg-1 by immunohistochemistry. We found that the expression of Drg-1 had a significant inverse correlation with the Gleason grading and the overall survival rate of patients. In particular, the gene expression in patients with lymph node or bone metastasis was significantly reduced as compared with those with localized prostate cancer, suggesting that the function of Drg-1 is negatively involved in metastatic progression of the disease. To further clarify the function of this gene in the advancement of prostate cancer, a spontaneous metastasis assay was performed in a severe combined immunodeficient (SCID) mouse model. We found that Drg-1 almost completely inhibited lung colonization of highly metastatic prostate cancer cells without affecting the growth of the primary tumors. These results strongly suggest that Drg-1 is a candidate metastasis suppressor gene for prostate cancer and may serve as a useful prognostic marker.

Published
2003

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