Cross talk between autophagy and oncogenic signaling pathways and implications for cancer therapy

Zada, Sahib; Hwang, Jin Seok; Ahmed, Mahmoud; Lai, Trang Huyen; Pham, Trang Minh; Elashkar, Omar; Kim, Deok Ryong

doi:10.1016/j.bbcan.2021.188565

Cited by 43 publications

(34 citation statements)

References 344 publications

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“…There was a complicated regulatory network between the regulation of EMT and autophagy. EMT-involved oncogenic signal proteins such as SNAI1, SLUG, ZEB1/2, and NOTCH1 were functionally related to autophagy ( Zada et al, 2021 ). Autophagy plays a tumor-inhibitory effect in the initial stages of carcinogenesis and a tumor-promotion function during the cancer progression ( White, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Increased ATG5 Expression Predicts Poor Prognosis and Promotes EMT in Cervical Carcinoma

Zhou

Wang

Ding

et al. 2021

Front. Cell Dev. Biol.

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Cervical cancer has the second-highest incidence and mortality of female malignancy. The major causes of mortality in patients with cervical cancer are invasion and metastasis. The epithelial–mesenchymal transition (EMT) process plays a major role in the acquisition of metastatic potential and motility. Autophagy-related genes (ARGs) are implicated in the EMT process, and autophagy exerts a dual function in EMT management at different phases of tumor progression. However, the role of specific ARGs during the EMT process has not yet been reported in cervical cancer. Based on the data from the Cancer Genome Atlas (TCGA) cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) sequencing database, we performed the prognosis analysis for those ARGs obtained from the Human Autophagy database. ATG5 was identified as the only important harmful marker influencing survival of cervical cancer patients by univariate Cox regression (HR 1.7; 95% CI: 1.0–2.8, p = 0.047), and the 5-years survival rate for the high- and low-ATG5 expression groups was 0.486 (0.375–0.631) and 0.782 (0.708–0.863), respectively. TCGA CESC methylation data showed that eight methylation sites of ATG5 could also be significantly associated with the overall survival (OS) of cervical cancer patients. Single-sample gene-set enrichment and gene functional enrichment results showed that ATG5 was correlated with some cancer-related pathways, such as phagocytosis-related genes, endocytosis-related genes, immune-related genes, EMT score, and some EMT signature-related genes. Next, cell migration and invasion assay and Western blot were applied to detect the function of ATG5 in EMT of cervical cancer. In cervical cancer cells, ATG5 knockdown resulted in attenuation of migration and invasion. The functional study showed that knockdown of ATG5 could reverse EMT process by P-ERK, P-NFκBp65, P-mTOR pathways, and so on. In conclusion, the present study implies that ATG5 was a major contributor to EMT regulation and poor prognosis in cervical cancer.

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Section: Introductionmentioning

confidence: 99%

Increased ATG5 Expression Predicts Poor Prognosis and Promotes EMT in Cervical Carcinoma

Zhou

Wang

Ding

et al. 2021

Front. Cell Dev. Biol.

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“…Autophagy, a typical cellular mechanism that represents a prospective therapeutic target in cancer treatment, is controlled by the PI3K/mTOR and AMPK signaling pathways [ 80 , 81 ]. In line with this, a study found that delphinidin can inhibit cell proliferation (IC 50 MDA-MB-453 (40 μM) and BT474 (100 μM)), increase apoptosis (upregulated caspase-3 and -9) and induce protective autophagy in HER2-positive breast cancer (MDA-MB-453 and BT474) cells by activating and suppressing the AMPK/ forkhead box O (FOXO) 3a and AKT/mTOR signaling pathways, respectively.…”

Section: Delphinidin and Anticancer Activitiesmentioning

confidence: 99%

Delphinidin and Its Glycosides’ War on Cancer: Preclinical Perspectives

Sharma

Choi

Kim

et al. 2021

IJMS

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Until now, several studies have looked at the issue of anthocyanin and cancer, namely the preventive and inhibitory effects of anthocyanins, as well as the underlying molecular processes. However, no targeted review is available regarding the anticarcinogenic effects of delphinidin and its glycosides on various cancers and their plausible molecular mechanisms. Considerable evidence shows significant anticancer properties of delphinidin-rich preparations and delphinidin alone both in vitro and in vivo. This review covers the in vitro and preclinical implications of delphinidin-mediated cell protection and cancer prevention; thus, we strongly recommend that delphinidin-rich preparations be further investigated as potential functional food, dietary antioxidant supplements, and natural health products targeting specific chronic diseases, including cancer. In addition to in vitro investigations, future research should focus on more animal and human studies to determine the true potential of delphinidin.

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“…Interestingly, the cell lines used in this study present different mutation patterns, including KRAS and TP53 (MiaPaCa-2 pancreatic ductal adenocarcinoma cells), PTEN and TP53 (Ishikawa endometrial adenocarcinoma cells), or TP53 mutations only (Hela cervical carcinoma cells). Our results suggest that autophagy induction by ERK5 inhibition is independent of Ras/Raf/ERK and PI3K-mTOR oncogenic pathways, two important cellular pathways that have been shown to regulate autophagy in cancer cells ( Zada et al, 2021 ). Numerous studies have shown that ERK5 inhibitors have antitumor activity by activating apoptosis in cancer cells and in tumor xenografts (reviewed in Gomez et al (2016) , Hoang et al (2017) , Stecca and Rovida (2019) ).…”

Section: Discussionmentioning

confidence: 66%

ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress

Gamez-Garcia

Bolinaga-Ayala

Yoldi

et al. 2021

Front. Cell Dev. Biol.

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Autophagy is a highly conserved intracellular process that preserves cellular homeostasis by mediating the lysosomal degradation of virtually any component of the cytoplasm. Autophagy is a key instrument of cellular response to several stresses, including endoplasmic reticulum (ER) stress. Cancer cells have developed high dependency on autophagy to overcome the hostile tumor microenvironment. Thus, pharmacological activation or inhibition of autophagy is emerging as a novel antitumor strategy. ERK5 is a novel member of the MAP kinase family that is activated in response to growth factors and different forms of stress. Recent work has pointed ERK5 as a major player controlling cancer cell proliferation and survival. Therefore small-molecule inhibitors of ERK5 have shown promising therapeutic potential in different cancer models. Here, we report for the first time ERK5 as a negative regulator of autophagy. Thus, ERK5 inhibition or silencing induced autophagy in a panel of human cancer cell lines with different mutation patterns. As reported previously, ERK5 inhibitors (ERK5i) induced apoptotic cancer cell death. Importantly, we found that autophagy mediates the cytotoxic effect of ERK5i, since ATG5ˉ/ˉ autophagy-deficient cells viability was not affected by these compounds. Mechanistically, ERK5i stimulated autophagic flux independently of the canonical regulators AMPK or mTORC1. Moreover, ERK5 inhibition resulted in ER stress and activation of the Unfolded Protein Response (UPR) pathways. Specifically, ERK5i induced expression of the ER luminal chaperone BiP (a hallmark of ER stress), the UPR markers CHOP and ATF4, and the spliced form of XBP1. Pharmacological inhibition of UPR with chemical chaperone TUDC, or ATF4 silencing, resulted in impaired ERK5i-mediated UPR, autophagy and cytotoxicity. Overall, our results suggest that ERK5 inhibition induces autophagy-mediated cancer cell death by activating ER stress. Since ERK5 inhibition sensitizes cancer cells and tumors to chemotherapy, future work will determine the relevance of UPR and autophagy in the combined use of chemotherapy and ERK5i to tackle Cancer.

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Cross talk between autophagy and oncogenic signaling pathways and implications for cancer therapy

Cited by 43 publications

References 344 publications

Increased ATG5 Expression Predicts Poor Prognosis and Promotes EMT in Cervical Carcinoma

Increased ATG5 Expression Predicts Poor Prognosis and Promotes EMT in Cervical Carcinoma

Delphinidin and Its Glycosides’ War on Cancer: Preclinical Perspectives

ERK5 Inhibition Induces Autophagy-Mediated Cancer Cell Death by Activating ER Stress

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