scholarly journals AURKA/NFκB Axis: A Key Determinant of Radioresistance in Cervical Squamous Carcinoma Cells

2021 ◽  
Author(s):  
Salini Das ◽  
Dilip Kumar Ray ◽  
Elizabeth Mahapatra ◽  
Souvick Biswas ◽  
Madhumita Roy ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Squamous Carcinoma ◽  
Aurora Kinase ◽  
Therapy Resistance ◽  
Squamous Carcinoma Cells ◽  
Cervical Cancer Cells ◽  
Induced Apoptosis

Abstract Background: Cervical cancer being one of the leading gynaecological cancers, possess a major threat by its ever-increasing trend of global recurrence events. Radioresistance is one of the major challenges confronted during the treatment of cervical cancer. Radioresistance in cancer cells is manifested by increased rate of cellular proliferation, migration-invasion and cell cycle alterations. Aurora Kinase A (AURKA), a mitotic serine/threonine kinase was found to be overexpressed in cancers and is associated with development of acquired therapy resistance. The principal objective of this study revolved with exploring the mechanisms by which AURKA confers radioadaptive response in cervical cancer cells. Methods and Results: Parental cervical squamous carcinoma cell line SiHa was subjected to recurrent insult by fractionated dose of X-irradiation. Finally, a resistant subline (SiHa/RR) was isolated at 40Gy. SiHa/RR exhibited higher expression of AURKA/ pAURKA along with the signaling molecules that are favored by this kinase (HIF1α, pAkt, NFκB) vis-à-vis lower expressions of the molecules that are generally suppressed by AURKA (p53, Gadd45a). Surprisingly, inhibition of AURKA in SiHa/RR showed improved radiosensitivity by reducing the wound healing capacity, sphere forming ability and enhancing radiation induced apoptosis. Ectopic overexpression of AURKA gave rise to radioresistant phenotype in parental SiHa by stimulating nuclear translocation of NFκB. This pattern of increased nuclear localization of NFκB was also observed in resistant subline as a consequence of activation and overexpression of AURKA. Conclusion: These findings strengthened the involvement of AURKA in radioresistance via activating NFκB mediated signaling pathway to deliver radioresistant associated adaptive complexities.

scholarly journals HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3

2020 ◽  
Vol 21 (17) ◽  
pp. 5976 ◽  
Author(s):  
Sang Ah Yi ◽  
Go Woon Kim ◽  
Jung Yoo ◽  
Jeung-Whan Han ◽  
So Hee Kwon
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Nuclear Export ◽  
Nuclear Translocation ◽  
Leptomycin B ◽  
P53 Signaling ◽  
Cervical Cancer Cells ◽  
Ubiquitin Conjugating Enzyme ◽  
The Stability

Cisplatin is the most frequently used agent for chemotherapy against cervical cancer. However, recurrent use of cisplatin induces resistance, representing a major hurdle in the treatment of cervical cancer. Our previous study revealed that HP1γ suppresses UBE2L3, an E2 ubiquitin conjugating enzyme, thereby enhancing the stability of tumor suppressor p53 specifically in cervical cancer cells. As a follow-up study of our previous findings, here we have identified that the pharmacological substances, leptomycin B and doxorubicin, can improve the sensitivity of cervical cancer cells to cisplatin inducing HP1γ-mediated elevation of p53. Leptomycin B, which inhibits the nuclear export of HP1γ, increased cisplatin-dependent apoptosis induction by promoting the activation of p53 signaling. We also found that doxorubicin, which induces the DNA damage response, promotes HP1γ-mediated silencing of UBE2L3 and increases p53 stability. These effects resulted from the nuclear translocation and binding of HP1γ on the UBE2L3 promoter. Doxorubicin sensitized the cisplatin-resistant cervical cancer cells, enhancing their p53 levels and rate of apoptosis when administered together with cisplatin. Our findings reveal a therapeutic strategy to target a specific molecular pathway that contributes to p53 degradation for the treatment of patients with cervical cancer, particularly with cisplatin resistance.

scholarly journals Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-26
Author(s):  
Liubing Hu ◽  
Yan Wang ◽  
Zui Chen ◽  
Liangshun Fu ◽  
Sheng Wang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Hela Cells ◽  
Cell Apoptosis ◽  
Hsp90 Inhibitor ◽  
Cervical Cancer Cells ◽  
Ros Scavenger ◽  
Induced Apoptosis ◽  
Human Cervical Cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells. However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies. Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed. In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells. Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic. Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells. Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53. ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-2112-induced p-JNK and p53. Moreover, SNX-2112 induced the upregulation of death-receptor DR5 in HeLa cells. The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL. In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells. The blockage of autophagy by bafilomycin A1 or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5. Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFTα were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway. Thus, the combination of SNX-2112 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance.

Benzobijuglone, a novel cytotoxic compound from Juglans mandshurica, induced apoptosis in HeLa cervical cancer cells

Phytomedicine ◽  
2007 ◽  
Vol 14 (12) ◽  
pp. 846-852 ◽  
Author(s):  
Zhi-Bo Li ◽  
Jing-Yun Wang ◽  
Bo Jiang ◽  
Xiu-Li Zhang ◽  
Li-Jia An ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Juglans Mandshurica ◽  
Cytotoxic Compound ◽  
Cervical Cancer Cells ◽  
Induced Apoptosis

Suppression of human 8-oxoguanine DNA glycosylase (OGG1) augments ultrasound-induced apoptosis in cervical cancer cells

Ultrasonics ◽  
2016 ◽  
Vol 72 ◽  
pp. 1-14
Author(s):  
Tao Xu ◽  
Yongli Nie ◽  
Jiao Bai ◽  
Linjun Li ◽  
Bo Yang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Dna Glycosylase ◽  
Cervical Cancer Cells ◽  
Induced Apoptosis

Mechanism of ricin-induced apoptosis in human cervical cancer cells

2005 ◽  
Vol 69 (5) ◽  
pp. 855-865 ◽  
Author(s):  
P.V. Lakshmana Rao ◽  
R. Jayaraj ◽  
A.S.B. Bhaskar ◽  
Om Kumar ◽  
R. Bhattacharya ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cervical Cancer Cells ◽  
Induced Apoptosis ◽  
Human Cervical Cancer Cells ◽  
Human Cervical Cancer

Inhibition of EGFR nuclear translocation attenuate radioresistance through decreased p-DNA-PK expression in cervical cancer cells.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17011-e17011
Author(s):  
Yunxiang Qi ◽  
Jinyi Lang ◽  
Lu Li ◽  
Mei Feng ◽  
Yecai Huang
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Dna Damage Repair ◽  
Cervical Cancer Cell Line ◽  
Phosphorylation Level ◽  
Damage Repair ◽  
Cervical Cancer Cells

e17011 Background: The commonly used treatment for cervical cancer is radiotherapy. However, the resistance to irradiation and metastasis at the advanced stage is a common reason for the poor prognosis and high mortality. This study was designed to elucidate the role of epidermal growth factor receptor (EGFR) nuclear translocation in radioresistance, and its correlation with DNA damage repair pathway in the cervical cancer cells. Methods: The dynamic expression of EGFR, DNA-dependent protein kinase (DNA-PK), PDK-1, PKN1 and their phosphorylation level in irradiated cervical cancer cell line CaSki at 0 10 20 40 minutes was determined by western blotting. Besides, nuclear localization signal (NLS) peptide inhibitor and control peptides was synthesized and treated cells before irradiation to elucidate the correlation between EGFR nuclear translocation and DNA damage repair after irradiation. Results: Expression of EGFR, protein kinase N1 (PKN1), and DNA-PK in nucleus was increased after irradiation in CaSki cells. Irradiation also enhanced the phosphorylation level of EGFR at Thr654, PKN1 at T774 and DNA-PK at T2609. Inhibition of EGFR nuclear translocation by NLS peptide decreased the expression level of EGFR and DNA-PK in the nucleus, and attenuated their phosphorylation process. Conclusions: EGFR nuclear translocation riggered by irradiation promoted DNA damage repair in irradiated cervical cancer cells. This work facilitated us to understand the possible molecular mechanism of the resistance to irradiation in the treatment of cervical cancer, providing a potentially potent clinical method to cancer therapy.

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