Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Herrmann, Anja L.; Kuhn, Bianca J.; Holzer, Angela; Krijgsveld, Jeroen; Hoppe‐Seyler, Karin; Hoppe‐Seyler, Felix

doi:10.3390/cancers13194995

Cited by 5 publications

(14 citation statements)

References 61 publications

(89 reference statements)

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“…We therefore analyzed FAM57A levels in cells seeded at LD or HD, which were cultivated either at normoxia or hypoxia. In addition, since the phenotype of hypoxic cervical cancer cells can be substantially influenced by glucose supply [ 4 , 7 , 27 ], cells were also cultivated at different glucose concentrations of 0 mM, 5.5 mM (corresponding to normal serum glucose concentrations in humans), or 25 mM. We regularly found that FAM57A was readily detectable in cells seeded at LD, but not in cells seeded at HD ( Figure 3 a).…”

Section: Resultsmentioning

confidence: 99%

“…Cells were fixed and stained with formaldehyde and crystal violet solution (12 mM crystal violet, 29 mM NaCl, 3.7% formaldehyde, 22% ethanol) 10 to 15 days after transfection. The areas occupied by colonies (colony area) were quantified in each dish by using an ImageJ macro (Damir Krunic, Light Microscopy Core Facility, DKFZ, Heidelberg, Germany) [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

“…For live cell imaging analyses, cells expressing nuclear mKate2 fluorescent protein (HeLa-1-mKate2, HeLa-2-mKate2, SiHa-mKate2 and CaSki-mKate2) were analyzed, which were generated as described previously [ 27 ]. All experiments were performed using the IncuCyte ® S3 Live-Cell Analysis System (Sartorius, Göttingen, Germany).…”

Section: Methodsmentioning

confidence: 99%

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FAM57A (Family with Sequence Similarity 57 Member A) Is a Cell-Density-Regulated Protein and Promotes the Proliferation and Migration of Cervical Cancer Cells

Yang

Strobel

Bulkescher

et al. 2022

Cells

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The FAM57A (family with sequence similarity 57 member A) gene is controversially discussed to possess pro- or anti-tumorigenic potential. Here, we analyze the regulation of cellular FAM57A protein levels and study the functional role of FAM57A in HPV-positive cervical cancer cells. We find that FAM57A protein expression strongly depends on cell density, with FAM57A being readily detectable at low cell density, but undetectable at high cell density. This regulation occurs post-transcriptionally and is not mirrored by corresponding changes at the RNA level. We further show that FAM57A protein levels are highly increased in cervical cancer cells cultivated at hypoxia compared to normoxia and provide evidence that FAM57A is a hypoxia-responsive gene under control of the α-subunit of the HIF-1 (hypoxia-inducible factor-1) transcription factor. Yet, the strong relative increase of FAM57A protein levels in hypoxic cells is predominantly cell-density-dependent and occurs post-transcriptionally. Other anti-proliferative effectors besides hypoxia, such as silencing of HPV E6/E7 oncogene expression in cervical cancer cells, also result in an increase of FAM57A levels compared to untreated cells. Functional analyses reveal that FAM57A repression leads to pronounced anti-proliferative as well as anti-migratory effects in cervical cancer cells. Taken together, these results provide insights into the regulation of FAM57A protein levels and reveal that they underlie a tight cell-density-dependent control. Moreover, they identify FAM57A as a critical determinant for the phenotype of cervical cancer cells, which promotes their proliferation and migration capacities.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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FAM57A (Family with Sequence Similarity 57 Member A) Is a Cell-Density-Regulated Protein and Promotes the Proliferation and Migration of Cervical Cancer Cells

Yang

Strobel

Bulkescher

et al. 2022

Cells

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“…CPX has been considered a potential antitumor agent due to its therapeutic potential in preclinical models of various cancers. For instance, CPX inhibits tumorigenesis by inducing apoptosis and protective autophagy in multiple cancers, such as colorectal cancer, glioma, and cervical carcinoma [ 7 , 9 , 25 , 41 ]. However, our study showed that CPX triggers autophagic death rather than apoptotic death in GC cells.…”

Section: Discussionmentioning

confidence: 99%

Ciclopirox drives growth arrest and autophagic cell death through STAT3 in gastric cancer cells

Chen

et al. 2022

Cell Death Dis

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Ciclopirox (CPX), an antifungal drug, has recently been identified as a promising agent for cancer treatment. However, the effects and underlying mechanism of CPX as an antitumor agent of gastric cancer (GC) remain largely unknown. Here, we found that CPX dramatically suppresses GC xenograft growth in vitro via inhibiting proliferation and stimulating autophagic cell death rather than apoptosis. Moreover, CPX (20 mg/kg, intraperitoneally) substantially inhibits GC xenograft tumor growth in vivo. Mechanistically, CPX promotes growth arrest and autophagic cell death through suppressing the phosphorylation of signal transducers and activators of transcription 3 (STAT3) at tyrosine 705 (Tyr705) and serine 727 (Ser727) sites, respectively. Additionally, CPX induces STAT3 ubiquitination, which subsequently leads to a decrease in the p-STAT3 (Ser727) level. On the other hand, CPX represses the p-STAT3 (Tyr705) level via p-Src (Tyr416) inhibition. Collectively, our findings unmask a novel mechanism by which CPX regulates growth and autophagic cell death in GC cells via regulating the phosphorylation of STAT3 both at Tyr705 and Ser727 residues, and suggest that CPX may be a potential treatment for GC.

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“…6,7 In accompanying proteome analyses, we found that CPX treatment leads to a strong reduction of signal transducer and activator of transcription 3 (STAT3) protein levels in HPV16-positive SiHa cervical cancer cells. 7 The STAT3 signaling cascade is hyperactive in approximately 70% of tumors and has been associated with multiple protumorigenic functions. For example, activated (Y705 phosphorylated) STAT3 can transcriptionally stimulate genes promoting tumor cell proliferation, survival, invasion, and metastasis.…”

Section: Introductionmentioning

confidence: 97%

Revisiting the role of endogenous STAT3 in HPV‐positive cervical cancer cells

Strobel,

Weber,

Heber

et al. 2023

Journal of Medical Virology

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Novel treatment options for human papillomavirus (HPV)‐induced cancers are urgently required. The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is considered to be constitutively active in HPV‐positive cervical cancer cells and essential for their proliferation. Moreover, STAT3 was reported to undergo mutually stimulatory interactions with the HPV E6/E7 oncogenes. Thus, inhibiting STAT3 in HPV‐positive cancer cells is under discussion to provide a powerful novel therapeutic strategy. We here show that the antifungal drug ciclopirox destabilizes the STAT3 protein by acting as an iron chelator. However, by exploring the functional consequences of STAT3 inhibition in HPV‐positive cancer cells, we obtained several unexpected results. Chemical STAT3 inhibitors heterogeneously affect cervical cancer cell proliferation and those which act antiproliferative also block the growth of STAT3 knockout cells, indicating induction of off‐target effects. In contrast to several chemical inhibitors, genetic inhibition of STAT3 expression by either RNA interference or the CRISPR/Cas9 method does not appreciably affect cervical cancer cell proliferation. Transcriptome analyses indicate that blocking STAT3 expression in HPV‐positive cancer cells has very limited effects on putative STAT3 target genes. Although the targeted inhibition of specific growth‐promoting signaling pathways leads to a feedback activation of STAT3 in cervical cancer cells via Janus kinase 1/2, this does not lead to treatment resistance. Moreover, we did not obtain experimental evidence for a STAT3‐linked activation of HPV E6/E7 oncogene expression or, vice versa, an E6/E7‐dependent activation of STAT3, at endogenous conditions in cervical cancer cells. Collectively, these findings question the essential role of STAT3 in cervical cancer cell proliferation and the strategy to inhibit STAT3 in these cells for therapeutic purposes.

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Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Cited by 5 publications

References 61 publications

FAM57A (Family with Sequence Similarity 57 Member A) Is a Cell-Density-Regulated Protein and Promotes the Proliferation and Migration of Cervical Cancer Cells

FAM57A (Family with Sequence Similarity 57 Member A) Is a Cell-Density-Regulated Protein and Promotes the Proliferation and Migration of Cervical Cancer Cells

Ciclopirox drives growth arrest and autophagic cell death through STAT3 in gastric cancer cells

Revisiting the role of endogenous STAT3 in HPV‐positive cervical cancer cells

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