Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma

Weng, Ningna; Qin, Siyuan; Liu, Jiayang; Huang, Xing; Jiang, Jingwen; Zhou, Li; Zhang, Zhe; Xie, Na; Wang, Kui; Park, Jin; Luo, Maochao; Peng, Liyuan; Nice, Edouard C.; Goel, Ajay; Han, Suxia; Huang, Canhua; Zhu, Qing

doi:10.1016/j.apsb.2022.01.018

Cited by 13 publications

(11 citation statements)

References 55 publications

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“…The generation of patient-derived organoid was performed as previously described [ 34 ]. Briefly, CRC tissue from patients was minced into small fragments (1–3 mm 3 ) pieces and digested by collagenase II and TrypLE Express Enzyme at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA

et al. 2022

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Background Hypoxia, a typical hallmark of solid tumors, exhibits an essential role in the progression of colorectal cancer (CRC), in which the dysregulation of long non-coding RNAs (lncRNAs) is frequently observed. However, the underlying mechanisms are not clearly defined. Methods The TCGA database was analyzed to identify differential lncRNA expression involved in hypoxia-induced CRC progression. qRT-PCR was conducted to validate the upregulation of lncRNA STEAP3-AS1 in CRC cell lines and tumor-bearing mouse and zebrafish models under hypoxia. ChIP-qRT-PCR was used to detect the transcriptional activation of STEAP3-AS1 mediated by HIF-1α. RNA-seq, fluorescent in situ hybridization, RNA pulldown, RNA immunoprecipitation, co-immunoprecipitation, immunofluorescence and immunoblot experiments were used to ascertain the involved mechanisms. Functional assays were performed in both in vitro and in vivo models to investigate the regulatory role of STEAP3-AS1/STEAP3/Wnt/β-catenin axis in CRC proliferation and metastasis. Results Here, we identified a hypoxia-induced antisense lncRNA STEAP3-AS1 that was highly expressed in clinical CRC tissues and positively correlated with poor prognosis of CRC patients. Upregulation of lncRNA STEAP3-AS1, which was induced by HIF-1α-mediated transcriptional activation, facilitated the proliferation and metastasis of CRC cells both in vitro and in vivo. Mechanistically, STEAP3-AS1 interacted competitively with the YTH domain-containing family protein 2 (YTHDF2), a N6-methyladenosine (m6A) reader, leading to the disassociation of YTHDF2 with STEAP3 mRNA. This effect protected STEAP3 mRNA from m6A-mediated degradation, enabling the high expression of STEAP3 protein and subsequent production of cellular ferrous iron (Fe2+). Increased Fe2+ levels elevated Ser 9 phosphorylation of glycogen synthase kinase 3 beta (GSK3β) and inhibited its kinase activity, thus releasing β-catenin for nuclear translocation and subsequent activation of Wnt signaling to support CRC progression. Conclusions Taken together, our study highlights the mechanisms of lncRNA STEAP3-AS1 in facilitating CRC progression involving the STEAP3-AS1/STEAP3/Wnt/β-catenin axis, which may provide novel diagnostic biomarkers or therapeutic targets to benefit CRC treatment. Graphical abstract Hypoxia-induced HIF-1α transcriptionally upregulates the expression of lncRNA STEAP3-AS1, which interacts competitively with YTHDF2, thus upregulating mRNA stability of STEAP3 and consequent STEAP3 protein expression. The enhanced STEAP3 expression results in production of cellular ferrous iron (Fe2+), which induces the Ser 9 phosphorylation and inactivation of GSK3β, releasing β-catenin for nuclear translocation and contributing to subsequent activation of Wnt signaling to promote CRC progression.

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Section: Methodsmentioning

confidence: 99%

Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA

et al. 2022

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“…60 However, dysfunctional autophagy induced by econazole can elicit ER stress. 61 In this study, the association between autophagy and aggravated ER stress was first studied to understand the signaling pathways involved in autophagy. The results indicate that the ATF4-TDDIT3-TRIB3-AKT-MTOR axis, which is mediated by ER stress, plays a crucial role in autophagosome formation (Figure 5).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the classical ER stressor tunicamycin enhances autophagic activity via the UPR effectors ATF4 and EIF2AK3 . However, dysfunctional autophagy induced by econazole can elicit ER stress . In this study, the association between autophagy and aggravated ER stress was first studied to understand the signaling pathways involved in autophagy.…”

Section: Discussionmentioning

confidence: 99%

Kuwanon H Inhibits Melanoma Growth through Cytotoxic Endoplasmic Reticulum Stress and Impaired Autophagy Flux

Hu,

Pan,

Luo

et al. 2023

J. Agric. Food Chem.

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Although great progress has been made recently in targeted and immune-based therapies, additional treatments are needed for most melanoma patients due to acquired chemoresistance, recurrence, or metastasis. Elevated autophagy is required for the pathogenesis of melanoma to attenuate metabolic stress, protecting cancer cells from chemotherapeutics or radiation. Thus, intervention with autophagy is a promising strategy for melanoma treatment. Here, we examined a novel antimelanoma natural compound named kuwanon H (KuH), which significantly inhibited melanoma cell growth in vitro/vivo. Mechanistically, KuH induced cytotoxic endoplasmic reticulum (ER) stress, which inhibited cell viability and induced apoptosis. Meanwhile, KuH-induced ER stress mediated autophagysome formation through the ATF4-DDIT3-TRIB3-AKT-MTOR axis. Importantly, KuH impaired autophagy flux, which contributed to the anticancer effects of KuH. Finally, our results showed that KuH enhanced the sensitivity of melanoma cells to cisplatin, both in vitro and in vivo, by impairing autophagy degradation of reactive oxygen species and damaged mitochondria. Our findings indicate that KuH is a promising candidate anticancer natural product for melanoma therapy.

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“…[26] To assess ROS generation, we Econazole is an anticancer drug with few side effects, and its mechanism is related to autophagosome accumulation and ER-stress(endoplasmic reticulum stress) mediated apoptosis. [27] The expression of autophagy-associated proteins was detected in response to PDT. The results are shown in Figure S4A (Supporting Information) (PANC-1 cells), Figure S4B (Supporting Information) (Pan02 cells) and Figure S4C (Supporting Information) (MIA-PACA-2 cells).…”

Section: Mechanism Of Action Of the Fbe Npsmentioning

confidence: 99%

Nano‐Econazole Enhanced PD‐L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma

Qin

Tian

et al. 2023

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Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo‐phototherapy nanoplatform is designed by which econazole and biliverdin can be co‐assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD‐L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin‐induced PTT/PDT and boost the immunotherapeutic response of PD‐L1 blockade. In addition, econazole simultaneously enhances PD‐L1 expression to sensitize anti‐PD‐L1 therapy, leading to suppression of distant tumors, long‐term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+T lymphocytes. The combined FBE NPs and α‐PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo‐phototherapy with PD‐L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

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Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma

Cited by 13 publications

References 55 publications

Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA

Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA

Kuwanon H Inhibits Melanoma Growth through Cytotoxic Endoplasmic Reticulum Stress and Impaired Autophagy Flux

Nano‐Econazole Enhanced PD‐L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma

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