Therapeutic Potential for Targeting Autophagy in ER+ Breast Cancer

Finnegan, Ryan; Elshazly, Ahmed M.; Schoenlein, Patricia V.; Gewirtz, David A.

doi:10.3390/cancers14174289

Cited by 18 publications

(35 citation statements)

References 78 publications

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“…Since the death was not from apoptosis in PAK4-knockdown hepatocarcinoma cells in our previous study (33), and p53 (25,26,34) and PAKs (16,19,21) were relevant with autophagy in cancer cells, the present study focused on autophagy. To date, main functional forms in autophagy are proposed to be cytotoxic, cytostatic, and cytoprotective in the context of antitumor therapy: cytotoxic autophagy leads to cancer cell death, cytostatic autophagy inhibits cancer cell propagation, and cytoprotective autophagy enhances cancer cells' drug sensitivity (35). Our findings showed an increased autophagosome by MDC staining and expression of autophagic biomarker LC3-II/LC3-I, suggesting an increased autophagy inhibiting propagation in PAK4knockdown HepG2 cells.…”

Section: Discussionmentioning

confidence: 53%

PAK4-relevant proliferation reduced by cell autophagy via p53/mTOR/p-AKT signaling

Li¹,

Wang²,

Wang³

et al. 2023

Transl Cancer Res

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Background: P21-activated kinase 4 (PAK4) involves in cell proliferation in cancer and mutually regulates with p53, a molecule is demonstrated to control cell autophagy by mammalian target of rapamycin (mTOR)/ protein kinase B (AKT) signaling. Since the signaling exhibits an association with PAK family members in cell autophagy, it implies that PAK4-relevant proliferation may be impacted by autophagy via p53 with a lack of evidence in cancer cells. Methods: In this research, transient and stable PAK4-knockdown human hepatocarcinoma cell lines (HepG2) were constructed by transfection of PAK4-RNA interference (RNAi) plasmid and lentivirus containing PAK4-RNAi plasmid, respectively. We investigated cell proliferation using methyl thiazolyl tetrazolium (MTT) and Cell Counting Kit 8 (CCK8) assays, cell cycle by flow cytometry (FCM) and cell autophagy by monodansylcadaverine (MDC) staining and autophagic biomarker's expression, and detected the expressions of p53, mTOR, phosphorylated-AKT (p-AKT) and AKT by immunofluorescence and western blot to explore the mechanism. Results: We successfully constructed transient and stable PAK4-knockdown HepG2 cell lines, and detected dysfunction of the cells' proliferation. An increased expression of p53, as a molecule of cell-cycle-surveillance on G1/S phase, was demonstrated in the cells although the cell cycle blocked at G2/M. And then, we detected increased autophagosome and autophagic biomarker LC3-II, and decreased expressions in p-AKT and mTOR. Conclusions:The proliferation is reduced in PAK4-knockdown HepG2 cells, which is relative to not only cell cycle arrest but also cell autophagy, and p53/mTOR/p-AKT signaling involves in the cell progress. The findings provide a new mechanism on PAK4 block in cancer therapy.

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Section: Discussionmentioning

confidence: 53%

PAK4-relevant proliferation reduced by cell autophagy via p53/mTOR/p-AKT signaling

Li¹,

Wang²,

Wang³

et al. 2023

Transl Cancer Res

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“…Thus, it would appear that sex, specifically sex hormones, may be the determining factor for the regulation of autophagy. Moreover, it is important to note that the upregulation of autophagy genes is beneficial to a certain degree, as it has been found to lead to cell death and cancer if overexpressed (Finnegan et al 2022).…”

Section: Discussionmentioning

confidence: 99%

Navigating sex and sex roles: deciphering sex-biased gene expression in a species with sex-role reversal (Syngnathus typhle)

Pappert

Dubin

Torres

et al. 2023

Preprint

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Sex-specific lifespan dimorphism is observed in many species, with females often outliving males. This is thought to be due to sex-specific and unequal resource allocation between reproduction and maintenance. However, most studies on ageing focus on animals with traditional sex roles, where females have the highest energy burden with both egg production and parental care. This leaves a gap in our understanding of how resource allocation and senescence are linked in species with non-traditional roles. To address this, we investigated the relationship between sex (biological) and sex role (behavioural) on resource allocation trade-offs in somatic maintenance in the broad-nosed pipefish Syngnathus typhle. This species is sex-role reversed, with males acting as the primary caretaker for offspring through their unique male pregnancy, providing the opportunity to decouple the roles of sex and sex role in resource allocation. Our results suggest that while some gene groups are influenced by sex roles (e.g., genome maintenance and immune defence), others depend on biological sex and hormones (e.g., energy and fat storage), with differences becoming more pronounced with age. These findings challenge traditional ageing theories and improve our understanding of how sex-specific differences in ageing are shaped.

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“…Autophagy is an adaptive response that tumor cells depend on for survival, particularly during periods of chemotherapeutic or targeted drug therapy. Protective autophagy, activated by numerous signaling pathways, supplies nutrition to cancer cells to maintain their growth and migration while also making them resistant to therapy [ 51 , 52 ]. As a result, autophagy suppression is often exploited as a target to increase cancer cell susceptibility to medicines.…”

Section: Natural Products Overcome Autophagy-mediated Tumor Drug Resi...mentioning

confidence: 99%

Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective

Yao

Feng

et al. 2022

Biomolecules

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Autophagy is a critical cellular adaptive response in tumor formation. Nutritional deficiency and hypoxia exacerbate autophagic flux in established malignancies, promoting tumor cell proliferation, migration, metastasis, and resistance to therapeutic interventions. Pro-survival autophagy inhibition may be a promising treatment option for advanced cancer. Furthermore, excessive or persistent autophagy is cytotoxic, resulting in tumor cell death. Targeted autophagy activation has also shown significant promise in the fight against tumor drug resistance. Several research groups have examined the ability of natural products (NPs) such as alkaloids, terpenoids, polyphenols, and anthraquinones to serve as autophagy inhibitors or activators. The data support the capacity of NPs that promote lethal autophagy or inhibit pro-survival autophagy from being employed against tumor drug resistance. This paper discusses the potential applications of NPs that regulate autophagy in the fight against tumor drug resistance, some limitations of the current studies, and future research needs and priorities.

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Therapeutic Potential for Targeting Autophagy in ER+ Breast Cancer

Cited by 18 publications

References 78 publications

PAK4-relevant proliferation reduced by cell autophagy via p53/mTOR/p-AKT signaling

PAK4-relevant proliferation reduced by cell autophagy via p53/mTOR/p-AKT signaling

Navigating sex and sex roles: deciphering sex-biased gene expression in a species with sex-role reversal (Syngnathus typhle)

Focusing on the Role of Natural Products in Overcoming Cancer Drug Resistance: An Autophagy-Based Perspective

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