RESUMO
MTP18 (also known as MTFP1), an inner mitochondrial membrane protein, plays a vital role in maintaining mitochondrial morphology by regulating mitochondrial fission. Here, we found that MTP18 functions as a mitophagy receptor that targets dysfunctional mitochondria into autophagosomes for elimination. Interestingly, MTP18 interacts with members of the LC3 (also known as MAP1LC3) family through its LC3-interacting region (LIR) to induce mitochondrial autophagy. Mutation in the LIR motif (mLIR) inhibited that interaction, thus suppressing mitophagy. Moreover, Parkin or PINK1 deficiency abrogated mitophagy in MTP18-overexpressing human oral cancer-derived FaDu cells. Upon exposure to the mitochondrial oxidative phosphorylation uncoupler CCCP, MTP18[mLIR]-FaDu cells showed decreased TOM20 levels without affecting COX IV levels. Conversely, loss of Parkin or PINK1 resulted in inhibition of TOM20 and COX IV degradation in MTP18[mLIR]-FaDu cells exposed to CCCP, establishing Parkin-mediated proteasomal degradation of outer mitochondrial membrane as essential for effective mitophagy. We also found that MTP18 provides a survival advantage to oral cancer cells exposed to cellular stress and that inhibition of MTP18-dependent mitophagy induced cell death in oral cancer cells. These findings demonstrate that MTP18 is a novel mitophagy receptor and that MTP18-dependent mitophagy has pathophysiologic implications for oral cancer progression, indicating inhibition of MTP18-mitophagy could thus be a promising cancer therapy strategy.
Assuntos
Membranas Mitocondriais , Neoplasias Bucais , Humanos , Apoptose/genética , Carbonil Cianeto m-Clorofenil Hidrazona/metabolismo , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Dinâmica Mitocondrial , Membranas Mitocondriais/metabolismo , Mitofagia/genética , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Autophagy is an intracellular catabolic self-cannibalism that eliminates dysfunctional cytoplasmic cargos by the fusion of cargo-containing autophagosomes with lysosomes to maintain cyto-homeostasis. Autophagy sustains a dynamic interlink between cytoprotective and cytostatic function during malignant transformation in a context-dependent manner. The antioxidant and immunomodulatory phyto-products govern autophagy and autophagy-associated signaling pathways to combat cellular incompetence during malignant transformation. Moreover, in a close cellular signaling circuit, autophagy regulates aberrant epigenetic modulation and inflammation, which limits tumor metastasis. Thus, manipulating autophagy for induction of cell death and associated regulatory phenomena will embark on a new strategy for tumor suppression with wide therapeutic implications. Despite the prodigious availability of lead pharmacophores in nature, the central autophagy regulating entities, their explicit target, as well as pre-clinical and clinical assessment remains a major question to be answered. In addition to this, the stage-specific regulation of autophagy and mode of action with natural products in regulating the key autophagic molecules, control of tumor-specific pathways in relation to modulation of autophagic network specify therapeutic target in caner. Moreover, the molecular pathway specificity and enhanced efficacy of the pre-existing chemotherapeutic agents in co-treatment with these phytochemicals hold high prevalence for target specific cancer therapeutics. Hence, the multi-specific role of phytochemicals in a cellular and tumor context dependent manner raises immense curiosity for investigating of novel therapeutic avenues. In this perspective, this review discusses about diverse implicit mechanisms deployed by the bioactive compounds in diagnosis and therapeutics approach during cancer progression with special insight into autophagic regulation.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Autofagia , Transformação Celular Neoplásica/metabolismo , Humanos , Lisossomos/patologia , Neoplasias/patologia , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêuticoRESUMO
Mitophagy is an evolutionarily conserved cellular process which selectively eliminates dysfunctional mitochondria by targeting them to the autophagosome for degradation. Dysregulated mitophagy results in the accumulation of damaged mitochondria, which plays an important role in carcinogenesis and tumor progression. The role of mitophagy receptors and adaptors including PINK1, Parkin, BNIP3, BNIP3L/NIX, and p62/SQSTM1, and the signaling pathways that govern mitophagy are impaired in cancer. Furthermore, the contribution of mitophagy in regulating the metabolic switch may establish a balance between aerobic glycolysis and oxidative phosphorylation for cancer cell survival. Moreover, ROS-driven mitophagy achieves different goals depending on the stage of tumorigenesis. Mitophagy promotes plasticity in the cancer stem cell through the metabolic reconfiguration for better adaption to the tumor microenvironment. In addition, the present review sheds some light on the role of mitophagy in stemness and differentiation during the transition of cell's fate, which could have a crucial role in cancer progression and metastasis. In conclusion, this review deals with the detailed molecular mechanisms underlying mitophagy, along with highlighting the dual role of mitophagy in different aspects of cancer, suggesting it as a possible target in the mitophagy-modulated cancer therapy.
Assuntos
Mitofagia/fisiologia , Neoplasias/patologia , Animais , Diferenciação Celular/fisiologia , Humanos , Mitocôndrias/patologia , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/fisiologiaRESUMO
Epigenetic alterations, such as DNA methylation, histone modifications and miRNAs, have a significant role play in malignant cellular transformation and metastasis. On the other hand, autophagy has been reported to perform context-dependent roles in cancer; at times, it becomes lethal and abolishes tumorigenesis, whereas, at other instances, it protects cancer cells by providing a rescue mechanism under adverse conditions. Although epigenetics and autophagy are two important and independent cellular processes, various oncogenic and oncosuppressor proteins involve autophagy through epigenetic modifications and different signaling pathways, thereby regulating tumor growth and therapeutic response. Moreover, the importance of epigenetic modification of autophagy in cancer is reflected through its involvement in cancer stem cell maintenance, which in turn, contributes to tumor cell viability during dormancy leading to tumor recurrence. The effects of epigenetic modifications of autophagy in cancer is still ambiguous and less acknowledged; therefore, efforts have been made to understand its detail underlying mechanism to unveil new targets and avenues for better prognosis and diagnosis of cancer.
Assuntos
Autofagia/genética , Epigênese Genética/genética , Neoplasias/genética , Animais , Sobrevivência Celular/genética , Histonas/genética , Humanos , MicroRNAs/genética , Prognóstico , Transdução de Sinais/genéticaRESUMO
Plant lectins are non-immunoglobin in nature and bind to the carbohydrate moiety of the glycoconjugates without altering any of the recognized glycosyl ligands. Plant lectins have found applications as cancer biomarkers for recognizing the malignant tumor cells for the diagnosis and prognosis of cancer. Interestingly, plant lectins contribute to inducing cell death through autophagy and apoptosis, indicating their potential implication in cancer inhibitory mechanism. In the present review, anticancer activities of major plant lectins have been documented, with a detailed focus on the signaling circuit for the possible molecular targeted cancer therapy. In this context, several lectins have exhibited preclinical and clinical significance, driving toward therapeutic potential in cancer treatment. Moreover, several plant lectins induce immunomodulatory activities, and therefore, novel strategies have been established from preclinical and clinical investigations for the development of combinatorial treatment consisting of immunotherapy along with other anticancer therapies. Although the application of plant lectins in cancer is still in very preliminary stage, advanced high-throughput technology could pave the way for the development of lectin-based complimentary medicine for cancer treatment.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Lectinas de Plantas/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Neoplasias/imunologia , Neoplasias/patologia , Lectinas de Plantas/farmacologiaRESUMO
Autophagy, an evolutionarily conserved process for maintaining the physio-metabolic equilibrium of cells, shares many common effector proteins with endocytosis. For example, tethering proteins involved in fusion like Ras-like GTPases (Rabs), soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs), lysosomal-associated membrane protein (LAMP), and endosomal sorting complex required for transport (ESCRT) have a dual role in endocytosis and autophagy, and the trafficking routes of these processes converge at lysosomes. These common effectors indicate an association between budding and fusion of membrane-bound vesicles that may have a substantial role in autophagic lysosome reformation, by sensing cellular stress levels. Therefore, autophagy-endocytosis crosstalk may be significant and implicates a novel endocytic regulatory pathway of autophagy. Moreover, endocytosis has a pivotal role in the intake of signalling molecules, which in turn activates cascades that can result in pathophysiological conditions. This review discusses the basic mechanisms of this crosstalk and its implications in order to identify potential novel therapeutic targets for various human diseases.
Assuntos
Autofagia/fisiologia , Endocitose/fisiologia , HumanosRESUMO
Dysregulation of the epigenome and constitutional epimutation lead to aberrant expression of the genes, which regulate cancer initiation and progression. Histone deacetylases (HDACs), which are highly conserved in yeast to humans, are known to regulate numerous proteins involved in the transcriptional regulation of chromatin structures, apoptosis, autophagy, and mitophagy. In addition, a non-permissive chromatin conformation is created by HDACs, preventing the transcription of the genes encoding the proteins associated with tumorigenesis. Recently, an expanding perspective has been reported from the clinical trials with HDACis (HDAC inhibitors), which has emerged as a determining target for the study of the detailed mechanisms underlying cancer progression. Therefore, the present review focuses on the comprehensive lucubration of post-translational modifications and the molecular mechanisms through which HDACs alter the ambiguities associated with epigenome, with particular insights into the initiation, progression, and regulation of cancer.