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The Role of Apoptosis and Autophagy in Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 January 2026) | Viewed by 8507

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Special Issue Editor

Dr. Souren Paul

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Guest Editor

The Hormel Institute, University of Minnesota, Austin, MN, USA
Interests: autophagy;cell death; colon cancer

Special Issue Information

Dear Colleagues,

Apoptosis, or programmed cell death, is the oldest known pathway of cell death. Previously, it was understood to involve morphological changes in cells that lead to death. Over the last three decades, extensive research has advanced our understanding of this pathway. Apoptosis in cancer cells mostly follows intrinsic or mitochondrial pathways in response to chemotherapeutic drugs. On the other hand, cytokines produced by immune cells induce an extrinsic pathway of cell death. Autophagy is a highly orchestrated lysosome-dependent process in cells that eliminates damaged organelles or proteins to maintain cellular homeostasis and survival. Numerous studies recognize autophagy as a double-edged sword in cancer. Cellular stress can activate autophagy, attenuate cellular processes, and lead to senescence. Autophagy can also help cancer cells to escape metabolic stress, promoting tumorigenesis. Recent advancements suggest that cancer cells activate autophagy in response to chemotherapeutic drugs as a pivotal mechanism of drug resistance. Recent research also suggests that using preclinical drugs to inhibit autophagy could be an attractive therapeutic opportunity for advanced-stage cancers. Recently, apoptosis–autophagy crosstalk has gained significant attention in actively growing cancer. Therefore, the targeting of these two pathways is still a significant avenue of research.

This Special Issue will cover all aspects of autophagy and apoptosis in cancer, including (but not limited to) the following:

Mechanisms of macroautophagy and mitophagy in cancer;
Mechanisms of different types of cell death in cancer;
Mechanisms of novel and FDA-approved drugs and immunotherapy in autophagy and apoptosis;
Crosstalk between autophagy and apoptosis in cancer.

Dr. Souren Paul
Guest Editor

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Keywords

apoptosis
cell death
tumor

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Published Papers (5 papers)

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Research

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18 pages, 13546 KB

Open AccessArticle

Pharmacological Modulation of Autophagy Can Sensitize Acute Lymphoblastic Leukemia Cell Lines to Dexamethasone

by Liliana Torres-López, Miguel Olivas-Aguirre, Alejandro Chávez-Gutiérrez and Oxana Dobrovinskaya

Cancers 2026, 18(5), 775; https://doi.org/10.3390/cancers18050775 - 28 Feb 2026

Viewed by 794

Abstract

Background: The potent synthetic glucocorticoid (GC), dexamethasone (DEX), is a highly effective component of conventional chemotherapy for acute lymphoblastic leukemia (ALL). However, cases of GC resistance require elucidation of the underlying mechanisms and the development of new strategies to overcome them. GC-induced autophagy can play a dual role in GC resistance: it often acts as a salvage mechanism in resistant cells, while in sensitive cells, it is a mechanism leading to cell death. Methods: In the present study, cell death and autophagy, as well as their dependence on glucocorticoid receptors (GRs), were simultaneously monitored in DEX-treated ALL cell lines, both sensitive and resistant to GCs. Results: In GC-resistant cell lines, no changes in autophagy levels were observed after DEX treatment, whereas in GC-sensitive cell lines, autophagy elevation was associated with cell death. Blockade of GC receptors completely abolished DEX cytotoxicity in CCRF–CEM cells but not in RS4;11 cells, suggesting the participation of distinct, cell line-specific mechanisms. Furthermore, we investigated how pharmacological modulation of autophagy, both induction and inhibition, affects GC sensitivity. Autophagy induction with tamoxifen (TAM) successfully sensitized most cell lines to DEX. In CCRF–CEM cells, the sensitization effect was shown to correlate with increased apoptosis. In other cell lines, no increase in cell death was observed, suggesting decreased cell proliferation. Conclusions: These results suggest that each ALL cell line may have an optimal basal level of autophagy, and targeted dysregulation of this level may be an effective strategy for enhancing GC sensitivity. Full article

(This article belongs to the Special Issue The Role of Apoptosis and Autophagy in Cancer)

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21 pages, 32710 KB

Open AccessArticle

Differences in Starvation-Induced Autophagy Response and miRNA Expression Between Rat Mammary Epithelial and Cancer Cells: Uncovering the Role of miR-218-5p

by Mateusz Gotowiec, Antoni Smoliński, Katarzyna Marcinkowska, Wiktor Pascal and Paweł Krzysztof Włodarski

Cancers 2025, 17(15), 2446; https://doi.org/10.3390/cancers17152446 - 23 Jul 2025

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Abstract

Background: Breast cancer (BC) is highly heterogeneous, with varying molecular characteristics, such as reliance on autophagy. Autophagy is a critical cellular degradation process that helps cells survive under stress, but its regulation can be influenced by altered microRNA (miRNA) expression. Studying miRNA changes during starvation-induced autophagy in both mammary epithelial cells and BC cells could reveal potential molecular therapy targets. Methods: Rat mammary gland healthy epithelial and cancer cells were subjected to starvation, and differences in proliferation, migration, invasion, autophagy, and expression of autophagy-associated miRNAs were determined. Afterward, we assessed the effects of miR-218-5p modulation on the aforementioned processes. Results: Starvation-induced autophagy reduced the proliferation of all cells and increased the invasive and migratory capacity of cancer cells (p ≤ 0.05). We identified a miRNA signature related to starvation, comprising twenty-seven miRNAs. One miRNA had a significantly elevated baseline expression, while another six, including miR-218-5p, had a significantly lower basal expression in cancer cells compared to healthy cells (p ≤ 0.05). However, starvation caused significant miRNA expression changes, with miR-218-5p being upregulated specifically in cancer cells (p = 0.20–0.01). Functional studies on the role of miR-218-5p show that its inhibition decreases migration and leads to autophagosome accumulation. The study of miR-218-5p molecular targets has shown that its inhibition of sorting nexin 18 (SNX18) may act as an important regulator of the starvation-induced response in cancer cells. Conclusions: The baseline expression of miRNA related to starvation and autophagy differs between rat mammary gland cancer and healthy cells. The response to starvation also varies between cancer cells and normal cells. Starvation induces BC-specific miRNA dysregulation, affecting particularly miR-218-5p, which acts via SNX18, promoting the cancer cells’ survival. Full article

(This article belongs to the Special Issue The Role of Apoptosis and Autophagy in Cancer)

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16 pages, 3003 KB

Open AccessArticle

Prognostic Value of LC3A Protein Expression Patterns in Rectal Cancer Tumors

by Vincent Ho, Liping Chung, Tristan Rutland, Vivienne Lea, Stephanie H. Lim, Askar Abubakar, Weng Ng, Mark Lee, Tara L. Roberts, Wei Chua, Scott Mackenzie and Cheok Soon Lee

Cancers 2025, 17(9), 1568; https://doi.org/10.3390/cancers17091568 - 5 May 2025

Viewed by 1374

Abstract

Background/Objectives: Autophagy is a conserved self-degradation process by which cells break down and recycle their cellular constituents. This process is activated by various stressors, including nutrient deprivation and DNA damage, and has also been associated with tumor progression. In the present study, we aimed to determine the expression patterns, clinicopathological significance, and prognostic value of the autophagy marker microtubule-associated protein 1 light chain 3 alpha (LC3A)—an essential component of autophagic vacuoles—in rectal cancer. Methods: LC3A reactivity was measured by immunohistochemistry in tumor samples from 243 patients who underwent surgery for rectal cancer. Results: Three distinct patterns of LC3A expression were identified: diffuse cytoplasmic, perinuclear, and stone-like structures (SLS). In Kaplan–Meier survival analyses, patients positive for the SLS pattern of LC3A staining in the tumor periphery (TP) had worse overall survival (OS; p = 0.001) and disease-free survival (DFS; p = 0.030) than those without SLSs in this region, as determined by the log–rank test. When patients were stratified by tumor stage, this result was significant in those with stage T3–T4 (OS, p < 0.001; DFS, p = 0.001) but not T1–T2 disease. Multivariate Cox regression analysis further showed an association between TP-localized LC3A SLS positivity and reduced OS for the overall cohort (hazard ratio [HR] = 2.6313, 95% confidence interval [CI]: 1.090–6.349, p = 0.031) and specifically those in the T3–T4 subgroup (HR = 3.347, 95% CI: 1.657–6.760, p = 0.001). Conclusions: Our findings suggest that positivity for SLSs in the TP may hold clinical value as a biomarker for survival prognosis in rectal cancer patients. Full article

(This article belongs to the Special Issue The Role of Apoptosis and Autophagy in Cancer)

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Review

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55 pages, 25547 KB

Open AccessReview

Autophagy–Apoptosis Crosstalk in Cancer: Mechanisms, Signaling Pathways, and Therapeutic Targeting

by Dia Kakkar, Saloni Saxena, Utkarshita Dhawan, Naman Dosi, Charvi Khanna and Souren Paul

Cancers 2026, 18(10), 1564; https://doi.org/10.3390/cancers18101564 - 12 May 2026

Viewed by 764

Abstract

Autophagy and apoptosis are two evolutionarily conserved catabolic processes that play important roles in maintaining cellular homeostasis and in determining cell fate when cells are exposed to various stresses in vivo. The interaction between autophagy and apoptosis has been studied extensively in cancer research, and it has been shown to affect cancer initiation and tumor formation, disease progression, therapeutic resistance, and overall survival. Autophagy typically functions as a cytoprotective mechanism in cancer cells subjected to metabolic, hypoxic, or therapeutic stress, whereas apoptosis primarily functions as an intrinsic programmed cell death pathway. While apoptosis and autophagy function as distinct pathways, there is significant molecular crosstalk, allowing cells to modulate their behavior from survival to death depending on the severity and duration of exposure to a given stressor and the cellular environment. This review examines the molecular landscape of the autophagy–apoptosis interplay in cancers, with special attention paid to the major signaling pathways involved and their biological outcomes in oncology. We examine the molecular mechanisms and signal transduction pathways involved in the crosstalk between autophagy and apoptosis in cancer. In particular, we focus on several key proteins that regulate this crosstalk, including kinases, caspases, heat shock proteins and transcription factors. Furthermore, we describe the major signal transduction pathways that regulate this crosstalk, including the PI3K/Akt/mTOR, MAPK, unfolded protein response, oxidative stress, and calcium signaling pathways. Additionally, we discussed how dysregulation of these pathways contributes to cancer progression and treatment resistance. Finally, we summarized the use of currently available therapeutic agents targeting the crosstalk between autophagy and apoptosis, including FDA-approved drugs and natural products, with the potential to enhance the effectiveness of anticancer treatments. A better understanding of this complex process will allow the development of new, precision-based, combination cancer therapies. Full article

(This article belongs to the Special Issue The Role of Apoptosis and Autophagy in Cancer)

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15 pages, 688 KB

Open AccessReview

Targeting Autophagy for Pituitary Tumors

by Evan Yin, Motoyasu Satou and Toru Tateno

Cancers 2025, 17(9), 1402; https://doi.org/10.3390/cancers17091402 - 23 Apr 2025

Viewed by 1786

Abstract

Pituitary tumors, arising from the pituitary gland, can be classified as functioning or non-functioning based on their hormone production. Previous studies demonstrated that impairment of cellular processes, such as autophagy, a crucial cellular recycling mechanism, has been implicated in pituitary tumorigenesis and hormone dysregulation. This review comprehensively examines the intricate relationship between autophagy and pituitary tumors. We explore the multifaceted role of autophagy in cancer, highlighting its dual nature as both a tumor suppressor and a promoter depending on the context. We also discuss the specific mechanisms of autophagy, including macroautophagy, mitophagy, crinophagy, and their relevance to pituitary tumorigenesis and hormone regulation. Furthermore, we analyze the current literature regarding the impact of various therapeutic interventions in pituitary tumor cells, with both autophagy-promoting and autophagy-inhibiting strategies. We address the challenges in interpreting autophagy activity and its complex interplay with hormone production. Current evidence suggests the potential of targeting autophagy as a therapeutic approach for pituitary tumors, emphasizing further research and clinical trials to determine the optimal strategy for individual patients and improve long-term outcomes. Full article

(This article belongs to the Special Issue The Role of Apoptosis and Autophagy in Cancer)

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