FoxM1 knockdown sensitizes human cancer cells to proteasome inhibitor-induced apoptosis but not to autophagy

Pandit, Bulbul; Gartel, Andrei L.

doi:10.4161/cc.10.19.17735

Cited by 31 publications

(28 citation statements)

References 20 publications

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“…The transcriptional level of FoxM1 can be down-regulate by the antibiotics siomycin A31 and thiostrepton32 by inhibition of proteasomal degradation of NRFM33. FoxM1 knockdown sensitizes cancer cells to proteasome inhibitor-induced apoptosis but not to autophagy34.…”

Section: Discussionmentioning

confidence: 99%

A lignan induces lysosomal dependent degradation of FoxM1 protein to suppress β-catenin nuclear translocation

Dong

Jeong

Lee

et al. 2017

Sci Rep

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Colon cancer is one of the most common cancers. In this study, we isolated a lignan [(−)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol, DFS] from Alnus japonica (Betulaceae) and investigated its biological activity and mechanism of action on colon cancer. DFS reduced the viability of colon cancer cells and induced cell cycle arrest. DFS also suppressed β-catenin nuclear translocation and β-catenin target gene expression through a reduction in FoxM1 protein. To assess the mechanism of the action of DFS, we investigated the effect of DFS on endogenous and exogenous FoxM1 protein degradation in colon cancer cells. DFS-induced FoxM1 protein degradation was suppressed by lysosomal inhibitors, chloroquine and bafilomycin A1, but not by knock-down of proteasomal proteins. The mechanism of DFS for FoxM1 degradation is lysosomal dependent, which was not reported before. Furthermore, we found that FoxM1 degradation was partially lysosomal-dependent under normal conditions. These observations indicate that DFS from A. japonica suppresses colon cancer cell proliferation by reducing β-catenin nuclear translocation. DFS induces lysosomal-dependent FoxM1 protein degradation. This is the first report on the lysosomal degradation of FoxM1 by a small molecule. DFS may be useful in treating cancers that feature the elevated expression of FoxM1.

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Section: Discussionmentioning

confidence: 99%

A lignan induces lysosomal dependent degradation of FoxM1 protein to suppress β-catenin nuclear translocation

Dong

Jeong

Lee

et al. 2017

Sci Rep

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show abstract

“…Earlier research has identified the negative regulation of the oncogenic transcription factor FoxM1 by proteasome inhibitors, thought to represent an important molecular factor involved in cancer cell-directed cytotoxicity of thiostrepton [28,62,63]. However, previous work documenting thiostrepton-modulation of FOXM1 expression in metastatic melanoma cells has only examined effects of prolonged exposure (≥ 24h exposure time) [30].…”

Section: Discussionmentioning

confidence: 99%

Thiostrepton is an inducer of oxidative and proteotoxic stress that impairs viability of human melanoma cells but not primary melanocytes

Qiao

Lamore

Cabello

et al. 2012

Biochemical Pharmacology

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Pharmacological induction of oxidative and proteotoxic stress has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells. Guided by a differential phenotypic drug screen for novel lead compounds that selectively induce melanoma cell apoptosis without compromising viability of primary human melanocytes, we have focused on the cyclic pyridinyl-polythiazolyl peptide-antimicrobial thiostrepton. Using comparative gene expression-array analysis, the early cellular stress response induced by thiostrepton was examined in human A375 metastatic melanoma cells and primary melanocytes. Thiostrepton displayed selective antimelanoma activity causing early induction of proteotoxic stress with massive upregulation of heat shock (HSPA6, HSPA1A, DNAJB4, HSPB1, HSPH1, HSPA1L, CRYAB, HSPA5, DNAJA1), oxidative stress (HMOX1, GSR, SOD1), and ER stress response (DDIT3) gene expression, confirmed by immunodetection (Hsp70, Hsp70B′, HO-1, phospho-eIF2α). Moreover, upregulation of p53, proapoptotic modulation of Bcl-2 family members (Bax, Noxa, Mcl-1, Bcl-2), and induction of apoptotic cell death were observed. Thiostrepton rapidly induced cellular oxidative stress followed by inactivation of chymotrypsin-like proteasomal activity and melanoma cell-directed accumulation of ubiquitinated proteins, not observed in melanocytes that were resistant to thiostrepton-induced apoptosis. Proteotoxic and apoptogenic effects were fully antagonized by antioxidant intervention. In RPMI 8226 multiple myeloma cells, known to be exquisitely sensitive to proteasome inhibition, early proteotoxic and apoptogenic effects of thiostrepton were confirmed by array analysis indicating pronounced upregulation of heat shock response gene expression. Our findings demonstrate that thiostrepton displays dual activity as a selective prooxidant and proteotoxic chemotherapeutic, suggesting feasibility of experimental intervention targeting metastatic melanoma and other malignancies including multiple myeloma.

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“…Additionally, along with its main role of stimulating cell cycle progression and cell growth, FOXM1 promotes angiogenesis [33,34] and contributes to metastasis by stimulating migration and invasion as well as epithelial-mesenchymal transition (EMT) [35][36][37]. Furthermore, FOXM1 counteracts senescence and increases tumor cell resistance to apoptosis [38][39][40]. FOXM1 also plays a role in promoting the expansion of undifferentiated cancer cells [41].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of FOXM1 Is a Potential Prognostic Marker in Male Breast Cancer

et al. 2017

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Background: Several studies have outlined biological differences between female and male breast cancer (MBC) and concluded that MBC should be considered as an entirely separate disease. Whether FOXM1 has any indication for prognosis in MBC patients remains unknown. We sought to examine the expression levels of FOXM1 in MBC and to identify the relationship between FOXM1 expression and patient survival. Patients and Methods: FOXM1 expression was evaluated in a total of 130 MBC specimens. Results: FOXM1 was overexpressed in 37% of the MBC samples. FOXM1 overexpression was significantly associated with tumor size (p = 0.045), histological grade (p = 0.048), lymph node metastasis (p = 0.012), Ki-67 proliferation index (p = 0.016), and molecular subtypes (p < 0.001). Multivariate analyses indicated that FOXM1 was an independent prognostic factor for overall survival in MBC patients (p < 0.001, hazard ratio = 0.69 (0.43-0.96)). Conclusions: Overexpression of FOXM1 was associated with well-established markers of poor prognosis; thus FOXM1 may represent a potential novel prognostic marker for MBC.

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FoxM1 knockdown sensitizes human cancer cells to proteasome inhibitor-induced apoptosis but not to autophagy

Cited by 31 publications

References 20 publications

A lignan induces lysosomal dependent degradation of FoxM1 protein to suppress β-catenin nuclear translocation

A lignan induces lysosomal dependent degradation of FoxM1 protein to suppress β-catenin nuclear translocation

Thiostrepton is an inducer of oxidative and proteotoxic stress that impairs viability of human melanoma cells but not primary melanocytes

Overexpression of FOXM1 Is a Potential Prognostic Marker in Male Breast Cancer

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