Role Of Autophagy In Cancer Research Articles

Autophagy modulation attenuates sorafenib resistance in HCC induced in rats

Hepatocellular carcinoma (HCC) has risen as the villain of cancer-related death globally, with a usual cruel forecasting. Sorafenib was officially approved by the FDA as first-line treatment for advanced HCC. Despite the brilliant promise revealed in research, actual clinical results are limited due to the widespread appearance of drug resistance. The tumor microenvironment (TME) has been correlated to pharmacological resistance, implying that existing cellular level strategies may be insufficient to improve therapy success. The role of autophagy in cancer is a two-edged sword. On one hand, autophagy permits malignant cells to overcome stress, such as hypoxic TME and therapy-induced starvation. Autophagy, on the other hand, plays an important role in damage suppression, which can reduce carcinogenesis. As a result, controlling autophagy is certainly a viable technique in cancer therapy. The goal of this study was to investigate at the impact of autophagy manipulation with sorafenib therapy by analyzing autophagy induction and inhibition to sorafenib monotherapy in rats with HCC. Western blot, ELISA, immunohistochemistry, flow cytometry, and quantitative-PCR were used to investigate autophagy, apoptosis, and the cell cycle. Routine biochemical and pathological testing was performed. Ultracellular features and autophagic entities were observed using a transmission electron microscope (TEM). Both regimens demonstrated significant reductions in chemotherapeutic resistance and hepatoprotective effects. According to the findings, both autophagic inhibitors and inducers are attractive candidates for combating sorafenib-induced resistance in HCC.

Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications.

Autophagy is a cytoplasmic defense mechanism that cells use to break and reprocess their intracellular components. This utilization of autophagy is regarded as a savior in nutrient-deficient and other stressful conditions. Hence, autophagy keeps contact with and responds to miscellaneous cellular tensions and diverse pathways of signal transductions, such as growth signaling and cellular death. Importantly, autophagy is regarded as an effective tumor suppressor because regular autophagic breakdown is essential for cellular maintenance and minimizing cellular damage. However, paradoxically, autophagy has also been observed to promote the events of malignancies. This review discussed the dual role of autophagy in cancer, emphasizing its influence on tumor survival and progression. Possessing such a dual contribution to the malignant establishment, the prevention of autophagycan potentially advocatefor the advancement of malignant transformation. In contrast, for the context of the instituted tumor, the agents of preventing autophagy potently inhibit the advancement of the tumor. Key regulators, including calpain 1, mTORC1, and AMPK, modulate autophagy in response to nutritional conditions and stress. Oncogenic mutations like RAS and B-RAF underscore autophagy's pivotal role in cancer development. The review also delves into autophagy's context-dependent roles in tumorigenesis, metastasis, and the tumor microenvironment (TME). It also discusses the therapeutic effectiveness of autophagy for several cancers. The recent implication of autophagy in the control of both innate and antibody-mediated immune systems made it a center of attention to evaluating its role concerning tumor antigens and treatments of cancer.

Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies.

The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.

Immunohistochemistry analysis of autophagy-related proteins Beclin-1, p62/SQSTM1, and LC3B in breast carcinoma progression to bone metastasis

Autophagy is a catabolic pathway involved both in tissue homeostasis and in cellular response to stress. The precise role of autophagy in cancer is still undefined and seems to depend on the tumor stage, appearing tumor-suppressive in physiological conditions and helpful to tumor progression in the established tumor. Here we analyzed by immunohistochemistry Beclin-1, p62, and LC3B, autophagic markers, in human specimens of normal breast, bone metastasis together with pair-matched invasive breast carcinoma of no special type (IBC-NST) as well as non-metastatic breast carcinoma, to disclose the possibility that they could be early prognostic indicators of the evolution of the disease toward the worst outcome. Different regions of metastatic carcinomas, i.e., areas adjacent to the tumor without signs of neoplastic growth, dysplastic lesions, and areas with invasive growth were considered. The pattern of autophagic parameters showed differences among the stages of breast carcinoma progression with a trend that indicated the activation of autophagic process in normal breast (Beclin-1 more elevated than p62), a pattern that was maintained in non-metastatic carcinoma. As the neoplasia proceeds with malignancy, the modification of the pattern of expression of autophagic markers (low ratio between Beclin-1 and p62) in areas of invasive growth of carcinomas suggested inhibition of the process. Of note, the parameters showed a different pattern in bone metastasis with respect to bone metastatic (bm)-IBC-NST, suggesting the reactivation of the autophagic process in the new growth site, helpful to the colonization. The course of autophagy markers during tumor progression could have a prognostic value towards bone metastasis and reveal different roles of the process in different phases of neoplastic growth. The understanding of the role of autophagy in bone metastasis could disclose new therapeutic targets to improve the conditions of patients.

Autophagy flux in bladder cancer: Cell death crosstalk, drug and nanotherapeutics

Autophagy, a self-digestion mechanism, has emerged as a promising target in the realm of cancer therapy, particularly in bladder cancer (BCa), a urological malignancy characterized by dysregulated biological processes contributing to its progression. This highly conserved catabolic mechanism exhibits aberrant activation in pathological events, prominently featured in human cancers. The nuanced role of autophagy in cancer has been unveiled as a double-edged sword, capable of functioning as both a pro-survival and pro-death mechanism in a context-dependent manner. In BCa, dysregulation of autophagy intertwines with cell death mechanisms, wherein pro-survival autophagy impedes apoptosis and ferroptosis, while pro-death autophagy diminishes tumor cell survival. The impact of autophagy on BCa progression is multifaceted, influencing metastasis rates and engaging with the epithelial-mesenchymal transition (EMT) mechanism. Pharmacological modulation of autophagy emerges as a viable strategy to impede BCa progression and augment cell death. Notably, the introduction of nanoparticles for targeted autophagy regulation holds promise as an innovative approach in BCa suppression. This review underscores the intricate interplay of autophagy with cell death pathways and its therapeutic implications in the nuanced landscape of bladder cancer.

Dual Role of Autophagy in Cancer: From Tumor Promotion to Suppression

Dual Role of Autophagy in Cancer: From Tumor Promotion to Suppression

Delineating the twin role of autophagy in lung cancer.

Autophagy represents an intracellular defense mechanism equipped within each eukaryotic cells to enable them to cope with variety of physical, chemical, and biological stresses. This mechanism helps to restore the homeostasis and preserve the cellular integrity and function of the cells. In these conditions, such as hypoxia, nutrient deprivation, inhibition of protein synthesis or microbial attack, the process of autophagy is upregulated to maintain cellular homeostasis. The role of autophagy in cancer is an intriguing topic which needs further exploration. This process of autophagy has been many times referred as a double-edged sword in the process of tumorigenesis. In the initial stages, it may act as a tumor suppressor and enable to quench the damaged organelles and harmful molecules generated. In more advanced stages, autophagy has been shown to act as a tumor-promoting system as it may help the cancer cells to cope better with stressful microenvironments. Besides this, autophagy has been associated with development of resistance to anticancer drugs as well as promoting the immune evasion in cancer cells, representing a serious obstacle in cancer treatment and its outcome. Also, autophagy is associated with hallmarks of cancer that may lead to activation of invasion and metastasis. The information on this twin role needs further exploration and deeper understanding of the pathways involved. In this review, we discuss the various aspects of autophagy during tumor development, from early to late stages of tumor growth. Both the protective role of autophagy in preventing tumor growth and the underlying mechanisms adopted with evidence from past studies have been detailed. Further, the role of autophagy in conferring resistance to distinct lung cancer treatment and immune shielding properties has also been discussed. This is essential for further improving on treatment outcome and success rates.

Autophagy and cancer: Basic mechanisms and inhibitor development.

Autophagy is a lysosomal degradation system of cytoplasmic components that contributes to cellular homeostasis through the turnover of various biomolecules and organelles, often in a selective manner. Autophagy is closely related to cancer, but its roles in cancer are complicated. It works as either a promoter or suppressor, depending on the stage and type of cancer. In this review, we briefly summarize the basic mechanisms of autophagy and describe the complicated roles of autophagy in cancer. Moreover, we summarize the clinical trials of autophagy inhibitors targeting cancer and the development of more specific autophagy inhibitors for future clinical application.

Crosstalk between autophagy and immune cell infiltration in the tumor microenvironment.

Autophagy is a conserved process for self-degradation and provides cells with a rescue mechanism to respond to circumstances such as stress and starvation. The role of autophagy in cancer is extremely complex and often paradoxical. Most of the related published studies on tumors are always focused on cancer cells. However, present studies gradually noticed the significance of autophagy in the tumor microenvironment. These studies demonstrate that autophagy and immunity work synergistically to affect tumor progression, indicating that autophagy could become a potential target for cancer immunotherapy. Therefore, it is crucial to clarify the correlation between autophagy and various tumor-infiltrating immune cells in the tumor microenvironment. The context-dependent role of autophagy is critical in the design of therapeutic strategies for cancer.

6-(Methylsulfonyl) Hexyl Isothiocyanate: A Chemopreventive Agent Inducing Autophagy in Leukemia Cell Lines.

Autophagy is a fundamental catabolic process of cellular survival. The role of autophagy in cancer is highly complex: in the early stages of neoplastic transformation, it can act as a tumor suppressor avoiding the accumulation of proteins, damaged organelles, and reactive oxygen species (ROS), while during the advanced stages of cancer, autophagy is exploited by cancer cells to survive under starvation. 6-(Methylsulfonyl) hexyl isothiocyanate (6-MITC) is the most interesting compound in the Wasabia Japonica rizhome. Recently, we proved its ability to induce cytotoxic, cytostatic, and cell differentiation effects on leukemic cell lines and its antimutagenic activity on TK6 cells. In the current study, to further define its chemopreventive profile, Jurkat and HL-60 cells were treated with 6-MITC for 24 h. The modulation of the autophagic process and the involvement of ROS levels as a possible trigger mechanisms were analyzed by flow cytometry. We found that 6-MITC induced autophagy in Jurkat and HL-60 cells at the highest concentration tested and increased ROS intracellular levels in a dose-dependent manner. Our results implement available data to support 6-MITC as an attractive potential chemopreventive agent.

Adipokines as Regulators of Autophagy in Obesity-Linked Cancer.

Excess body weight and obesity have become significant risk factors for cancer development. During obesity, adipose tissue alters its biological function, deregulating the secretion of bioactive factors such as hormones, cytokines, and adipokines that promote an inflammatory microenvironment conducive to carcinogenesis and tumor progression. Adipokines regulate tumor processes such as apoptosis, proliferation, migration, angiogenesis, and invasion. Additionally, it has been found that they can modulate autophagy, a process implicated in tumor suppression in healthy tissue and cancer progression in established tumors. Since the tumor-promoting role of autophagy has been well described, the process has been suggested as a therapeutic target in cancer. However, the effects of targeting autophagy might depend on the tumor type and microenvironmental conditions, where circulating adipokines could influence the role of autophagy in cancer. Here, we review recent evidence related to the role of adipokines in cancer cell autophagy in an effort to understand the tumor response in the context of obesity under the assumption of an autophagy-targeting treatment.

Unveiling the Noncanonical Autophagy-Independent Role of ATG7 and ATG9B in Head and Neck Squamous Cell Carcinoma (HNSCC).

The role of autophagy in cancer remains elusive, and nontargeted autophagy inhibitors have limited therapeutic effects in HNSCC. Here, we systematically analyzed the correlation of autophagy-related genes in HNSCC through TCGA and single-cell sequencing data (GSE103322). ATG9B and ATG7 were found to have noncanonical autophagy-independent functions in HNSCC. Specifically, ATG9B was a protective factor in HNSCC patients through downregulating cancer cell EMT, and ATG7 was correlated with the immunosuppressive environment in HNSCC. Mechanistically, single-cell analysis revealed that ATG9B increased the epithelial phenotype of cancer cells but did not influence EMT signaling pathways. ATG7 was strongly correlated with elevated immunosuppressive checkpoints like PD-1, PD-L1, and CTLA4 in HNSCC. Further single-cell analysis and multiple immunofluorescence colocalization analyses indicated that ATG7 contributed to the high expression of PD-L1 in myeloid cells but not cancer cells. Collectively, our results revealed noncanonical autophagy-independent functions of autophagy-related genes. These results increase understanding of the intricacies of autophagy and may contribute to precision treatment using autophagy-targeted therapies.

Sirtuin 4 activates autophagy and inhibits tumorigenesis by upregulating the p53 signaling pathway

The role of autophagy in cancer is context-dependent. In the present study, we aimed to investigate the regulator and underlying mechanism of autophagy. We found that a sirtuin (SIRT) family member, SIRT4, was significantly associated autophagy pathway in pancreatic ductal adenocarcinoma (PDAC). Specifically, in vitro cell culture experiments and in vivo transgenic and xenografted animal models revealed that SIRT4 could inhibit tumor growth and promote autophagy in PDAC. In terms of the mechanism, we demonstrated that SIRT4 activated the phosphorylation of p53 protein by suppressing glutamine metabolism, which was crucial in SIRT4-induced autophagy. AMPKα was implicated in the regulation of autophagy and phosphorylation of p53 mediated by SIRT4, contributing to the suppression of pancreatic tumorigenesis. Notably, the clinical significance of the SIRT4/AMPKα/p53/autophagy axis was demonstrated in human PDAC specimens. Collectively, these findings suggested that SIRT4-induced autophagy further inhibited tumorigenesis and progression of PDAC, highlighting the potential of SIRT4 as a therapeutic target for cancer.

AMBRA1 and its role as a target for anticancer therapy.

The activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1) is an intrinsically disordered protein that regulates the survival and death of cancer cells by modulating autophagy. Although the roles of autophagy in cancer are controversial and context-dependent, inhibition of autophagy under some circumstances can be a useful strategy for cancer therapy. As AMBRA1 is a pivotal autophagy-associated protein, targeting AMBRA1 similarly may be an underlying strategy for cancer therapy. Emerging evidence indicates that AMBRA1 can also inhibit cancer formation, maintenance, and progression by regulating c-MYC and cyclins, which are frequently deregulated in human cancer cells. Therefore, AMBRA1 is at the crossroad of autophagy, tumorigenesis, proliferation, and cell cycle. In this review, we focus on discussing the mechanisms of AMBRA1 in autophagy, mitophagy, and apoptosis, and particularly the roles of AMBRA1 in tumorigenesis and targeted therapy.

Effects of Autophagy-Related Genes on the Prognosis and Immune Microenvironment of Ovarian Cancer.

Ovarian cancer (OC) is among the most malignant tumors of the female reproductive system. The role of autophagy in cancer is complex, and the functional relationship between autophagy-related genes and OC remains unclear. Here, the prognostic value of autophagy-related genes in OC and relationships between autophagy and immune function were evaluated. OC data from The Cancer Genome Atlas and the Human Autophagy Database were obtained to identify autophagy-related genes. Univariate and multivariate Cox analyses were used to construct a prognostic model based on autophagy-related genes. Relationships between risk scores and clinical traits were evaluated. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Cytoscape were used to analyze gene functions and their effects on the immune microenvironment. Relationships between autophagy genes and long noncoding RNAs (lncRNAs) were evaluated by Pearson's correlation coefficients, and lncRNAs corresponding to the autophagy-related genes associated with OC prognosis were used to construct a model. Relationships between risk scores and survival and prognosis were evaluated. Finally, a gene set enrichment analysis was performed. Seven autophagy-related genes (CAPN1, CDKN1B, DNAJB1, GNAI3, MTMR14, RHEB, and SIRT2) were identified as independent predictors of prognosis. Three lncRNAs corresponding to autophagy genes independently influenced prognosis. Autophagy genes are closely related to immunity. Fifteen immune cell types showed different levels of infiltration between the high- and low-risk groups. Moreover, immune cell infiltration differed between the high- and low-risk groups based on the model. Our analysis of genes and lncRNAs related to prognosis clarifies the role of autophagy in OC and provides a theoretical basis for further research.

Modulation of Autophagy in Adrenal Tumors.

Adrenal masses are one of the most common tumors in humans. The majority are benign and non-functioning and therefore do not require immediate treatment. In contrast, the rare adrenal malignant tumors are often highly aggressive and with poor prognosis. Besides usually being detected in advanced stages, often already with metastases, one of the reasons of the unfavorable outcome of the patients with adrenal cancer is the absence of effective treatments. Autophagy is one of the intracellular pathways targeted by several classes of chemotherapeutics. Mitotane, the most commonly used drug for the treatment of adrenocortical carcinoma, was recently shown to also modulate autophagy. Autophagy is a continuous programmed cellular process which culminates with the degradation of cellular organelles and proteins. However, being a dynamic mechanism, understanding the autophagic flux can be highly complex. The role of autophagy in cancer has been described paradoxically: initially described as a tumor pro-survival mechanism, different studies have been showing that it may result in other outcomes, namely in tumor cell death. In adrenal tumors, this dual role of autophagy has also been addressed in recent years. Studies reported both induction and inhibition of autophagy as a treatment strategy of adrenal malignancies. Importantly, most of these studies were performed using cell lines. Consequently clinical studies are still required. In this review, we describe what is known about the role of autophagy modulation in treatment of adrenal tumors. We will also highlight the aspects that need further evaluation to understand the paradoxical role of autophagy in adrenal tumors.

ATG7 is a haploinsufficient repressor of tumor progression and promoter of metastasis

The role of autophagy in cancer is complex. Both tumor-promoting and tumor-suppressive effects are reported, with tumor type, stage and specific genetic lesions dictating the role. This calls for analysis in models that best recapitulate each tumor type, from initiation to metastatic disease, to specifically understand the contribution of autophagy in each context. Here, we report the effects of deleting the essential autophagy gene Atg7 in a model of pancreatic ductal adenocarcinoma (PDAC), in which mutant KrasG12D and mutant Trp53172H are induced in adult tissue leading to metastatic PDAC. This revealed that Atg7 loss in the presence of KrasG12D/+ and Trp53172H/+ was tumor promoting, similar to previous observations in tumors driven by embryonic KrasG12D/+ and deletion of Trp53. However, Atg7 hemizygosity also enhanced tumor initiation and progression, even though this did not ablate autophagy. Moreover, despite this enhanced progression, fewer Atg7 hemizygous mice had metastases compared with animals wild type for this allele, indicating that ATG7 is a promoter of metastasis. We show, in addition, that Atg7+/- tumors have comparatively lower levels of succinate, and that cells derived from Atg7+/- tumors are also less invasive than those from Atg7+/+ tumors. This effect on invasion can be rescued by ectopic expression of Atg7 in Atg7+/- cells, without affecting the autophagic capacity of the cells, or by treatment with a cell-permeable analog of succinate. These findings therefore show that ATG7 has roles in invasion and metastasis that are not related to the role of the protein in the regulation of autophagy.

Dichotomous role of autophagy in cancer.

Autophagy is an evolutionary conserved catabolic process that plays physiological and pathological roles in a cell. Its effect on cellular metabolism, the proteome, and the number and quality of organelles, diversely holds the potential to alter cellular functions. It acts paradoxically in cancer as a tumor inhibitor as well as a tumor promoter. In the early stage of tumorigenesis, it prevents tumor initiation by the so-called "quality control mechanism" and suppresses cancer progression. For late-staged tumors that are exposed to stress, it acts as a vibrant process of degradation and recycling that promotes cancer by facilitating metastasis. Despite this dichotomy, the crucial role of autophagy is evident in cancer, and associated with mammalian targets of rapamycin (mTOR), p53, and Ras-derived major cancer networks. Irrespective of the controversy regarding autophagic manipulation, promotion and suppression of autophagy act as potential therapeutic targets in cancer treatment and may provide various anticancer therapies.

The multifaceted role of autophagy in cancer.

Autophagy is a cellular degradative pathway that plays diverse roles in maintaining cellular homeostasis. Cellular stress caused by starvation, organelle damage, or proteotoxic aggregates can increase autophagy, which uses the degradative capacity of lysosomal enzymes to mitigate intracellular stresses. Early studies have shown a role for autophagy in the suppression of tumorigenesis. However, work in genetically engineered mouse models and in vitro cell studies have now shown that autophagy can be either cancer-promoting or inhibiting. Here, we summarize the effects of autophagy on cancer initiation, progression, immune infiltration, and metabolism. We also discuss the efforts to pharmacologically target autophagy in the clinic and highlight future areas for exploration.

Autophagy in acute myeloid leukemia: a paradoxical role in chemoresistance.

Autophagy is a lysosomal degradation pathway that is constitutively active in almost every cell of our body at basal level. This self-eating process primarily serves to remove superfluous constituents of the cells and recycle the degraded products. Autophagy plays an essential role in cell homeostasis and can be enhanced in response to stressful conditions. Impairment in the regulation of the autophagic pathway is implicated in pathological conditions such as neurodegeneration, cardiac disorders, and cancer. However, the role of autophagy in cancer initiation and development is controversial and context-dependent. Evidence from various studies has shown that autophagy serves dual purpose and may assist in cancer progression or suppression. In the early stages of cancer initiation, autophagy acts as a quality control mechanism and prevents cancer development. When cancer is established and progresses to a later stage, autophagy helps in the survival of these cells through adaptation to stresses, including exposure to anti-cancer drugs. In this review, we highlight various studies on autophagic pathways and describe the role of autophagy in cancer, specifically acute myeloid leukemia (AML). We also discuss the prognostic significance of autophagy genes involved in AML leukemogenesis and implications in conferring resistance to chemotherapy.