scholarly journals Phytochemical library screen reveals betulinic acid as a novel Skp2‐SCF E3 ligase inhibitor in non‐small cell lung cancer

2021 ◽  
Author(s):  
Dan‐Hua He ◽  
Yu‐Fei Chen ◽  
Yi‐Le Zhou ◽  
Shi‐Bing Zhang ◽  
Ming Hong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Betulinic Acid ◽  
E3 Ligase ◽  
Small Cell ◽  
Small Cell Lung ◽  
Library Screen

Hypoxia increases the apoptotic response to betulinic acid and betulin in human non-small cell lung cancer cells

2021 ◽  
Vol 333 ◽  
pp. 109320
Author(s):  
Justyna Kutkowska ◽  
Leon Strzadala ◽  
Andrzej Rapak
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Betulinic Acid ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Small Cell Lung ◽  
Apoptotic Response

scholarly journals Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non‐small cell lung cancer cells

2017 ◽  
Vol 108 (11) ◽  
pp. 2265-2272 ◽  
Author(s):  
Justyna Kutkowska ◽  
Leon Strzadala ◽  
Andrzej Rapak
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Betulinic Acid ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Synergistic Activity ◽  
Small Cell Lung

scholarly journals Combination Treatment With Inhibitors of ERK and Autophagy Enhances Antitumor Activity of Betulinic Acid in Non–small-Cell Lung Cancer In Vivo and In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Chao-Yue Sun ◽  
Di Cao ◽  
Qian-Nan Ren ◽  
Shan-Shan Zhang ◽  
Ning-Ning Zhou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Betulinic Acid ◽  
Small Cell ◽  
Small Cell Lung ◽  
Autophagy Inhibition

Aberrant activation of the Ras–ERK signaling pathway drives many important cancer phenotypes, and several inhibitors targeting such pathways are under investigation and/or approved by the FDA as single- or multi-agent therapy for patients with melanoma and non–small-cell lung cancer (NSCLC). Here, we show that betulinic acid (BA), a natural pentacyclic triterpenoid, inhibits cell proliferation, and induces apoptosis and protective autophagy in NSCLC cells. Thus, the cancer cell killing activity of BA is enhanced by autophagy inhibition. Mitogen-activated protein kinases, and especially ERK that facilitates cancer cell survival, are also activated by BA treatment. As such, in the presence of ERK inhibitors (ERKi), lung cancer cells are much more sensitive to BA. However, the dual treatment of BA and ERKi results in increased protective autophagy and AKT phosphorylation. Accordingly, inhibition of AKT has a highly synergistic anticancer effect with co-treatment of BA and ERKi. Notably, autophagy inhibition by hydroxychloroquine (HCQ) increases the response of lung cancer cells to BA in combination with ERKi. In vivo, the three-drug combination (BA, ERKi, and HCQ), resulted in superior therapeutic efficacy than single or dual treatments in the xenograft mouse model. Thus, our study provides a combined therapy strategy that is a highly effective treatment for patients with NSCLC.

Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer

2019 ◽  
Vol 14 (3) ◽  
pp. 318-326 ◽  
Author(s):  
Yanfei Zhang ◽  
Xinchun Zhao ◽  
Yongchun Zhou ◽  
Min Wang ◽  
Guangbiao Zhou
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
E3 Ligase ◽  
Small Cell ◽  
Small Cell Lung ◽  
Encoding Gene

scholarly journals HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1

2020 ◽  
Author(s):  
Niko Moses ◽  
Mu Zhang ◽  
Jheng-Yu Wu ◽  
Chen Hu ◽  
Shengyan Xiang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
E3 Ligase ◽  
Radiation Sensitivity ◽  
Small Cell ◽  
Cell Cycle Checkpoint ◽  
Small Cell Lung ◽  
M Phase

ABSTRACTWe previously discovered that HDAC6 regulates the DNA damage response via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6’s ubiquitin E3 ligase activity. Here, we have reported HDAC6’s second E3 ligase substrate, a critical cell cycle checkpoint protein, Chk1. We have found that HDAC6 and Chk1 directly interact, and that HDAC6 ubiquitinates Chk1 in vivo. Typical Chk1 protein levels fluctuate, peaking at G2 and subsequently resolving via the ubiquitin-proteasome pathway. However, in HDAC6 knockdown cells, Chk1 is constitutively active and fails to resolve post-ionizing radiation (IR), leading to increased radiation sensitivity. Upon IR treatment, a greater proportion of HDAC6 knockdown cells accumulated at G2/M phase when compared with control cells. Depletion or inhibition of Chk1 in HDAC6 knockdown cells renders those cells radiosensitive, suggesting that persistently high level of Chk1 could lead cells to arrest at G2/M phase and eventually, apoptosis. Clinically, we found that high levels of phosphorylated Chk1 (p-Ser317) are associated with a better overall survival in a cohort of non-small cell lung cancer (NSCLC) patients, suggesting a link between active Chk1 and lung cancer development. Overall, our results highlight a novel mechanism of Chk1 regulation at the protein level, and a possible strategy for sensitizing NSCLC to radiation via inhibiting the activity of HDAC6’s E3 ligase.

scholarly journals Targeted Inhibition of the E3 Ligase SCFSkp2/Cks1 Has Antitumor Activity in RB1-Deficient Human and Mouse Small-Cell Lung Cancer

2020 ◽  
Vol 80 (11) ◽  
pp. 2355-2367
Author(s):  
Hongling Zhao ◽  
Niloy J. Iqbal ◽  
Vineeth Sukrithan ◽  
Cari Nicholas ◽  
Yingjiao Xue ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Antitumor Activity ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
E3 Ligase ◽  
Small Cell ◽  
Small Cell Lung ◽  
Targeted Inhibition ◽  
Human And Mouse

scholarly journals HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2237
Author(s):  
Niko Moses ◽  
Mu Zhang ◽  
Jheng-Yu Wu ◽  
Chen Hu ◽  
Shengyan Xiang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
E3 Ligase ◽  
Small Cell ◽  
Cell Cycle Checkpoint ◽  
Small Cell Lung ◽  
Ubiquitin E3 Ligase

We have previously discovered that HDAC6 regulates the DNA damage response (DDR) via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6’s ubiquitin E3 ligase activity. Here, we have reported HDAC6’s second potential E3 ligase substrate, a critical cell cycle checkpoint protein, Chk1. We have found that HDAC6 and Chk1 directly interact, and that HDAC6 ubiquitinates Chk1 in vivo and in vitro. Specifically, HDAC6 interacts with Chk1 via the DAC1 domain, which contains its ubiquitin E3 ligase activity. During the cell cycle, Chk1 protein levels fluctuate, peaking at the G2 phase, subsequently resolving via the ubiquitin-proteasome pathway, and thereby allowing cells to progress to the M phase. However, in HDAC6 knockdown non-small cell lung cancer (NSCLC) cells, Chk1 is constitutively active and fails to resolve post-ionizing radiation (IR), and this enhanced Chk1 activity leads to preferential G2 arrest in HDAC6 knockdown cells accompanied by a reduction in colony formation capacity and viability. Depletion or pharmacological inhibition of Chk1 in HDAC6 knockdown cells reverses this radiosensitive phenotype, suggesting that the radiosensitivity of HDAC6 knockdown cells is dependent on increased Chk1 kinase activity. Overall, our results highlight a novel mechanism of Chk1 regulation at the post-translational level, and a possible strategy for sensitizing NSCLC to radiation via inhibiting HDAC6’s E3 ligase activity.

Small cell lung cancer

2001 ◽  
Vol 37 ◽  
pp. 61-63
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung

Non-small cell lung cancer

2001 ◽  
Vol 37 ◽  
pp. 47-61
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung
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