Chloroquine promotes gefitinib‑induced apoptosis by inhibiting protective autophagy in cutaneous squamous cell carcinoma

Ou, Chengshan; Liu, Hongxia; Ding, Zhenhua; Zhou, Liang

doi:10.3892/mmr.2019.10734

Cited by 8 publications

(10 citation statements)

References 25 publications

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“… 3 , 12 , 13 , 14 , 15 Various cytoprotective processes, including glutaminolysis, are involved in attenuating TKI-induced cytotoxicity. 16 , 17 , 18 , 19 Hence, we examined whether overexpression of miR-634 enhances TKI-induced cytotoxicity. When A431 cells were transfected with increasing doses (1.0–10 nM) of miR-634 and simultaneously treated with gefitinib (1–30 μM), capase-3/7 activity gradually increased in a dose-dependent manner compared with cells treated with gefitinib only ( Figure 4 A).…”

Section: Resultsmentioning

confidence: 99%

“… 14 TKI-induced cytotoxicity is attenuated by various cytoprotective cell survival processes, including anti-apoptosis signaling, antioxidant scavenging, and autophagy. 16 , 17 , 18 , 19 Furthermore, glutaminolysis, a metabolic process involving glutamine utilization that produces ATP as an energy source and glutathione (GSH) as a reactive oxygen species (ROS) scavenger, is also involved in attenuating TKI-induced cytotoxicity. 20 , 21 Therefore, negatively modulating these cytoprotective processes may be a reasonable strategy for improving the efficacy of EGFR TKIs in cSCC.…”

Section: Introductionmentioning

confidence: 99%

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Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with miR-634 Ointment

Inoue

Fujiwara

Hamamoto

et al. 2020

Molecular Therapy - Oncolytics

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For cutaneous squamous cell carcinoma (cSCC), topical treatment is an essential option for patients who are not candidates for, or who refuse, surgery. Epidermal growth factor receptor (EGFR) plays a key role in the development of cSCC, but EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have shown only partial clinical benefit in this disease. Thus, there is an unmet need to develop novel strategies for improving the efficacy of TKIs in cSCC. We previously demonstrated that the tumor-suppressive microRNA (miRNA) miR-634 functions as a negative modulator of the cytoprotective cancer cell survival processes and is a useful anticancer therapeutic agent. In the present study, we found that topical application of an ointment containing miR-634 inhibited in vivo tumor growth without toxicity in a cSCC xenograft mouse model and a 7,12-dimethylbenz[ a ]anthracene (DMBA)/12- O -tetradecanoylphorbol-13-acetate (TPA)-induced papilloma mouse model. Functional validation revealed that miR-634 overexpression reduced glutaminolysis by directly targeting ASCT2 , a glutamine transporter. Furthermore, overexpression of miR-634 synergistically enhanced TKI-induced cytotoxicity by triggering severe energetic stress in vitro and in vivo . Thus, we propose that topical treatment with miR-634 ointment is a useful strategy for improving for EGFR TKI-based therapy for cSCC.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with miR-634 Ointment

Inoue

Fujiwara

Hamamoto

et al. 2020

Molecular Therapy - Oncolytics

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“…The role of autophagy is interesting but complicated because it can cause unintended consequences (e.g., cancer-promoting or cancer-suppressing effects) [40] . On the one hand, given the genomic instability and degradation of vital components, autophagy inhibits tumor growth and induces apoptosis because of abnormal transformations [41] . On the other hand, the clearance and recycling of dysfunctional organelles and proteins provide energy for tumor cells.…”

Section: Chloroquine As An Anticancer Agentmentioning

confidence: 99%

Chloroquine against malaria, cancers and viral diseases

Zhou

Wang

Yang

et al. 2020

Drug Discovery Today

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“…Cutaneous squamous cell carcinoma (cSCC) is a malignant tumor that originates from epidermal or appendage keratinocytes ( 1 ). cSCC primarily occurs in the elderly population in light-exposed areas, including the scalp, face and back of the hands ( 2 ). cSCC is not life threatening, but if left untreated can grow larger or spread to other organs causing serious complications, local lymph node metastases and distant metastases ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

lncRNA EZR‑AS1 knockdown represses proliferation, migration and invasion of cSCC via the PI3K/AKT signaling pathway

Lü

Sun

et al. 2020

Mol Med Rep

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Although long non-coding RNAs (lncRNAs) have been implicated in various human cancer types, the role of lncRNA ezrin antisense RNA 1 (EZR-AS1) in cutaneous squamous cell carcinoma (cSCC) remains unclear. The present study aimed to investigate the effect of lncRNAEZR-AS1 on cSCC and identify the underlying molecular mechanisms. EZR-AS1 expression was measured in cSCC tissue and cells detected using reverse transcription-quantitative PCR. Gain-of-function assays were performed in A431 cells, which have a relatively low expression of EZR-AS1, while loss-of-function assays were performed in SCC13 and SCL-1 colon cancer cells, which have a relatively high expression of EZR-AS1. Cell viability, proliferation, migration, invasion and apoptosis were assessed using MTT, plate cloning, wound healing, Transwell and flow cytometry assays, respectively. EZR-AS1 mRNA expression levels were significantly upregulated in cSCC tissues and cells compared with adjacent healthy tissues and HaCaT cells, respectively. Compared with the small interfering RNA (si)-negative control (NC) group, si-EZR-AS1 significantly inhibited SCC13 and SCL-1 cell proliferation, migration and invasion, but promoted cell apoptosis. By contrast, compared with the pc-NC group, EZR-AS1 overexpression significantly enhanced A431 cell proliferation, migration and invasion, but inhibited cell apoptosis. Moreover, focal adhesion kinase (FAK) was identified as a target of EZR-AS1, and EZR-AS1 knockdown significantly decreased FAK expression compared with the si-NC group. Moreover, EZR-AS1 knockdown significantly downregulated the protein expression levels of phosphorylated (p)-PI3K/PI3K and p-AKT/AKT in cSCC cells compared with the si-NC group. The PI3K agonist 740Y-P significantly reversed si-EZR-AS1-mediated effects on SCC13 and SCL-1 cell proliferation, migration, invasion and apoptosis. In conclusion, the present study demonstrated that si-EZR-AS1 inhibited cSCC cell proliferation, migration and invasion, and promoted cell apoptosis, potentially via regulating the PI3K/AKT signaling pathway. Therefore, the present study provided novel insights into the diagnosis and treatment of cSCC.

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Chloroquine promotes gefitinib‑induced apoptosis by inhibiting protective autophagy in cutaneous squamous cell carcinoma

Cited by 8 publications

References 25 publications

Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with miR-634 Ointment

Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with miR-634 Ointment

Chloroquine against malaria, cancers and viral diseases

lncRNA EZR‑AS1 knockdown represses proliferation, migration and invasion of cSCC via the PI3K/AKT signaling pathway

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