scholarly journals ATG 4B Serves a Crucial Role in RCE-4-Induced Inhibition of the Bcl-2–Beclin 1 Complex in Cervical Cancer Ca Ski Cells

2021 ◽  
Vol 22 (22) ◽  
pp. 12302
Author(s):  
Fang-fang You ◽  
Jing Zhang ◽  
Fan Cheng ◽  
Kun Zou ◽  
Xue-qing Zhang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Cells ◽  
Molecular Mechanism ◽  
Crucial Role ◽  
Beclin 1 ◽  
Steroidal Saponin ◽  
Immunoprecipitation Assay

RCE-4, a steroidal saponin isolated from Reineckia carnea, has been studied previously and has exhibited promising anti-cervical cancer properties by inducing programmed cell death (PCD) of Ca Ski cells. Considering the cancer cells developed various pathways to evade chemotherapy-induced PCD, there is, therefore, an urgent need to further explore the potential mechanisms underlying its actions. The present study focused on targeting the Bcl-2–Beclin 1 complex, which is known as the key regulator of PCD, to deeply elucidate the molecular mechanism of RCE-4 against cervical cancer. The effects of RCE-4 on the Bcl-2–Beclin 1 complex were investigated by using the co-immunoprecipitation assay. In addition, autophagy-related genes (ATG) were also analyzed due to their special roles in PCD. The results demonstrated that RCE-4 inhibited the formation of the Bcl-2–Beclin 1 complex in Ca Ski cells via various pathways, and ATG 4B proteins involved in this process served as a key co-factor. Furthermore, based on the above, the sensitivity of RCE-4 to Ca Ski cells was significantly enhanced by inhibiting the expression of the ATG 4B by applying the ATG 4B siRNA plasmid.

The role of programmed cell death ligand-1/ programmed cell death-1 (PD-L1/PD-1) in HPV-induced cervical cancer and potential for their use in blockade therapy

2020 ◽  
Vol 27 ◽  
Author(s):  
Lifang Zhang ◽  
Yu Zhao ◽  
Quanmei Tu ◽  
Xiangyang Xue ◽  
Xueqiong Zhu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Escape ◽  
Hypoxia Inducible Factor ◽  
Hpv Infection ◽  
Advanced Cervical Cancer ◽  
Cervical Carcinogenesis ◽  
Programmed Cell Death 1

Background: Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. Methods: We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. Results: One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signaling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and MicroRNAs, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in immune escape of cervical cancer through inhibition of host immune response. creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PD-L1/PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. Conclusion: Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body’s immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.

scholarly journals SOG1 transcription factor promotes the onset of endoreduplication under salinity stress in Arabidopsis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kalyan Mahapatra ◽  
Sujit Roy
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Transcription Factor ◽  
Programmed Cell Death ◽  
Salinity Stress ◽  
Crucial Role ◽  
Genome Stability ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Regulators

AbstractAs like in mammalian system, the DNA damage responsive cell cycle checkpoint functions play crucial role for maintenance of genome stability in plants through repairing of damages in DNA and induction of programmed cell death or endoreduplication by extensive regulation of progression of cell cycle. ATM and ATR (ATAXIA-TELANGIECTASIA-MUTATED and -RAD3-RELATED) function as sensor kinases and play key role in the transmission of DNA damage signals to the downstream components of cell cycle regulatory network. The plant-specific NAC domain family transcription factor SOG1 (SUPPRESSOR OF GAMMA RESPONSE 1) plays crucial role in transducing signals from both ATM and ATR in presence of double strand breaks (DSBs) in the genome and found to play crucial role in the regulation of key genes involved in cell cycle progression, DNA damage repair, endoreduplication and programmed cell death. Here we report that Arabidopsis exposed to high salinity shows generation of oxidative stress induced DSBs along with the concomitant induction of endoreduplication, displaying increased cell size and DNA ploidy level without any change in chromosome number. These responses were significantly prominent in SOG1 overexpression line than wild-type Arabidopsis, while sog1 mutant lines showed much compromised induction of endoreduplication under salinity stress. We have found that both ATM-SOG1 and ATR-SOG1 pathways are involved in the salinity mediated induction of endoreduplication. SOG1was found to promote G2-M phase arrest in Arabidopsis under salinity stress by downregulating the expression of the key cell cycle regulators, including CDKB1;1, CDKB2;1, and CYCB1;1, while upregulating the expression of WEE1 kinase, CCS52A and E2Fa, which act as important regulators for induction of endoreduplication. Our results suggest that Arabidopsis undergoes endoreduplicative cycle in response to salinity induced DSBs, showcasing an adaptive response in plants under salinity stress.

IFT20 confers paclitaxel resistance by triggering β-arrestin-1 to modulate ASK1 signaling in breast cancer

2021 ◽  
Author(s):  
Ni Qiu ◽  
Huan Jin ◽  
Lulu Cui ◽  
Yong-tao Zhan ◽  
Hao-ming Xia ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Molecular Mechanism ◽  
Breast Cancer Cells ◽  
Feedback Inhibition ◽  
In Vivo Studies ◽  
Paclitaxel Resistance ◽  
Western Blots ◽  
Paclitaxel Treatment

Abstract Background: System paclitaxel-based chemotherapy is the first-line treatment regimen of defense against breast cancer, but inherent or acquired chemotherapy resistance remains a major obstacle in breast cancer therapy. Elucidating the molecular mechanism of chemoresistance is essential to improve the outcome of patients with breast cancer. Methods: Paclitaxel sensitivity was first evaluated using models of IFT20 deletion and overexpression of breast cancer cells in vitro and in vivo studies to identify the effect of IFT20 on paclitaxel chemoresistance. To delineate the molecular mechanism of IFT20 contributions to paclitaxel chemoresistance, changes in ASK signaling and its downstream JNK cascades expression were quantified using western blots, and the potential involvement of β-arrestin-1 was investigated using co-IP studies. Results: IFT20 is positively associated with shorter relapse-free survival in patients with system paclitaxel-based chemotherapy. High expressed IFT20 in breast cancer cells increases resistance to cell death upon paclitaxel treatment; in contrast, IFT20 knockdown enhances apoptosis in breast cancer cells in response to paclitaxel. Mechanistically, IFT20 triggers β-arrestin-1 to bind with ASK1 and promotes the ubiquitination of ASK1 degradation, leading to attenuating ASK1 signaling and its downstream JNK cascades, which helped cells to escape from cell death during paclitaxel treatment. Conclusion: IFT20 confers to paclitaxel chemoresistance. It interacts with β-arrestin-1 to mediate ubiquitination of ASK1 for feedback inhibition of ASK1/JNK signaling and restrains paclitaxel-induced apoptosis. These findings identify IFT20 as a promising novel target for overcoming paclitaxel resistance in breast cancer.

Immunotherapy in combination with PARP inhibition in advanced cervical cancer patients functionally competent or deficient for the Fanconi anemia repair pathway.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5597-TPS5597
Author(s):  
John Paul Diaz ◽  
Wenrui Duan ◽  
Eric Schroeder ◽  
Zuanel Diaz ◽  
Nicholas Lambrou ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Dna Repair ◽  
Programmed Cell Death ◽  
Phase Ii ◽  
Fanconi Anemia ◽  
Objective Response ◽  
Repair Pathway ◽  
Mutational Burden ◽  
Tumor Mutational Burden

TPS5597 Background: Immunotherapy has improved outcomes for patients with recurrent or metastatic cervical cancer whose tumors express PD-L1. Pembrolizumab (PEM), a monoclonal antibody that binds to programmed cell death 1 (PD 1) receptor, inhibits interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). It is approved for the treatment of recurrent or metastatic cervical cancer. Despite promising results, new strategies are being developed to improve immunotherapy responses. This includes DNA-damaging agents that have the potential to enhance the response to immunotherapy by promoting neo-antigen release, increasing tumor mutational burden, and enhancing PD-L1 expression. Poly-ADP-ribose polymerase (PARP) inhibitors, such as olaparib, have shown synergy with immunotherapy in preclinical and early clinical studies. PARP-based therapy is based on the inhibition of single-strand DNA repair, leading to DNA damage and increased tumor mutational burden. As a result, the tumor becomes a more attractive target for immunotherapy. Based on this, we are investigating the interplay between homologous recombination (HR) repair deficiency, another mechanism of DNA repair, and solid tumor response to ICI. Our approach uses an all-inclusive functional immunofluorescence assay of the Fanconi Anemia triple-staining immunofluorescence (FATSI) we developed and can be performed in paraffin-embedded tumors. Methods: This is a phase II open-label single center trial evaluating the role of PEM and olaparib in patients with metastatic cervical cancer who have progressed on first-line standard of care chemotherapy. FATSI will be performed in all patients. We hypothesize that FATSI negative tumors will be associated with improved responses. Other eligibility criteria include measurable disease by imaging, 18 years of age or older, and no previous exposure to ICI or PARP inhibitor. The primary objective is to evaluate the immune-related objective response rate (iORR) achieved in patients with FA Repair Pathway functionally competent and functionally deficient tumors. Secondary objectives include 20-week progression free survival and overall survival. Other exploratory objectives include evaluation of the mutation load and markers of neo-antigenicity, T cell receptor clonotype analyses (before and after treatment), and alterations in HR repair genes. We will utilize a two-stage phase II design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%, represents a response by chance alone or other infrequent unknown mechanisms. An interim analysis requires at least 2 of the first 20 evaluable patients enrolled have an objective response. If this occurs, we will accrue 28 additional patients to total 48. Enrollment is ongoing and two patients are currently on treatment. Clinical trial information: NCT04483544.

scholarly journals Macrophage Autophagy and Oxidative Stress: An Ultrastructural and Immunoelectron Microscopical Study

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Ida Perrotta ◽  
Valentina Carito ◽  
Emilio Russo ◽  
Sandro Tripepi ◽  
Saveria Aquila ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Defense Mechanisms ◽  
Ultrastructural Localization ◽  
Microscopical Study ◽  
Beclin 1 ◽  
Cell Organelles ◽  
A Cell ◽  
First Time

The word autophagy broadly refers to the cellular catabolic processes that lead to the removal of damaged cytosolic proteins or cell organelles through lysosomes. Although autophagy is often observed during programmed cell death, it may also serve as a cell survival mechanism. Accumulation of reactive oxygen species within tissues and cells induces various defense mechanisms or programmed cell death. It has been shown that, besides inducing apoptosis, oxidative stress can also induce autophagy. To date, however, the regulation of autophagy in response to oxidative stress remains largely elusive and poorly understood. Therefore, the present study was designed to examine the ratio between oxidative stress and autophagy in macrophages after oxidant exposure (AAPH) and to investigate the ultrastructural localization of beclin-1, a protein essential for autophagy, under basal and stressful conditions. Our data provide evidence that oxidative stress induces autophagy in macrophages. We demonstrate, for the first time by immunoelectron microscopy, the subcellular localization of beclin-1 in autophagic cells.

scholarly journals Active elimination of intestinal cells drives oncogenic growth in organoids

2020 ◽  
Author(s):  
Ana Krotenberg Garcia ◽  
Arianna Fumagalli ◽  
Huy Quang Le ◽  
Owen J. Sansom ◽  
Jacco van Rheenen ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Fate ◽  
Crucial Role ◽  
Intestinal Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Cell Competition ◽  
Type Population

AbstractCompetitive cell-interactions play a crucial role in quality control during development and homeostasis. Here we show that cancer cells use such interactions to actively eliminate wild-type intestine cells in enteroid monolayers and organoids. This apoptosis-dependent process boosts proliferation of intestinal cancer cells. The remaining wild-type population activates markers of primitive epithelia and transits to a fetal-like state. Prevention of this cell fate transition avoids elimination of wild-type cells and, importantly, limits the proliferation of cancer cells. JNK signalling is activated in competing cells and is required for cell fate change and elimination of wild-type cells. Thus, cell competition drives growth of cancer cells by active out-competition of wild-type cells through forced cell death and cell fate change in a JNK dependent manner.

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