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Autophagy, a classical cellular degradative catabolic process, also involves a functionally discrete non-degradative role in eukaryotic cells. It imparts critical regulatory function on conventional and unconventional protein secretion (degradative and secretory autophagy with distinct lysosomal degradation and extracellular expulsion, respectively) pathways. The N-amino terminal leader sequence containing proteins follows a conventional secretion pathway, while the leader-less proteins opt for secretory autophagy. The secretory autophagic process ensembles core autophagy machinery proteins, specifically ULK1/2, Beclin 1, LC3, and GABARAP, in coordination with Golgi re-assembly and stacking proteins (GRASPs). The secretory omegasomes fuse with the plasma membrane for the expulsion of cytosolic cargos to the extracellular environment. Alternatively, the secretory omegasomes also fuse with multi-vesicular bodies (MVBs) and harmonize ESCRTs (Complex I; TSG101) and Rab GTPase for their release to extracellular space. Autophagy has been associated with the secretion of diverse proteins involved in cellular signaling, inflammation, and carcinogenesis. Secreted proteins play an essential role in cancer by sustaining cell proliferation, inhibiting apoptosis, enhancing angiogenesis and metastasis, immune cell regulation, modulation of cellular energy metabolism, and resistance to anticancer drugs. The complexity of autophagy regulation during tumorigenesis is dependent on protein secretion pathways. Autophagy-regulated TOR-autophagy spatial coupling compartment complex energizes enhanced secretion of pro-inflammatory cytokines and leaderless proteins such as HMGB1. In conclusion, the chapter reviews the role of autophagy in regulating conventional and unconventional protein secretion pathways and its possible role in cancer., Competing Interests: Conflict of interest statement The authors declare that they have no conflict of interest in this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lysosomes are single membrane-bound organelles containing acid hydrolases responsible for the degradation of cellular cargo and maintenance of cellular homeostasis. Lysosomes could originate from pre-existing endolysosomes or autolysosomes, acting as a critical juncture between autophagy and endocytosis. Stress that triggers lysosomal membrane permeabilization can be altered by ESCRT complexes; however, irreparable damage to the membrane results in the induction of a selective lysosomal degradation pathway, specifically lysophagy. Lysosomes play an indispensable role in different types of autophagy, including microautophagy, macroautophagy, and chaperone-mediated autophagy, and various cell death pathways such as lysosomal cell death, apoptotic cell death, and autophagic cell death. In this review, we discuss lysosomal reformation, maintenance, and degradation pathways following the involvement of the lysosome in autophagy and cell death, which are related to several pathophysiological conditions observed in humans., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Tumour-promoting inflammation is a critical hallmark in cancer development, and inflammasomes are well-known regulators of inflammatory processes within the tumour microenvironment. Different inflammasome components along with the adaptor, apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC), and the effector, caspase-1, have a significant influence on tumorigenesis but in a tissue-specific and stage-dependent manner. The downstream products of inflammasome activation, that is the proinflammatory cytokines such as IL-1β and IL-18, regulate tissue homeostasis and induce antitumour immune responses, but in contrast, they can also favour cancer growth and proliferation by directing various oncogenic signalling pathways in cancer cells. Moreover, different epigenetic mechanisms, including DNA methylation, histone modification and noncoding RNAs, control inflammasomes and their components by regulating gene expression during cancer progression. Furthermore, autophagy, a master controller of cellular homeostasis, targets inflammasome-induced carcinogenesis by maintaining cellular homeostasis and removing potential cancer risk factors that promote inflammasome activation in support of tumorigenesis. Here, in this review, we summarize the effect of inflammasome activation in cancers and discuss the role of epigenetic and autophagic regulatory mechanisms in controlling inflammasomes. A proper understanding of the interactions among these key processes will be useful for developing novel therapeutic regimens for targeting inflammasomes in cancer. [ABSTRACT FROM AUTHOR]

Aberrant DNA hypermethylation is associated with oral carcinogenesis. Procaine, a local anesthetic, is a DNA methyltransferase (DNMT) inhibitor that activates anticancer mechanisms. However, its effect on silenced tumor suppressor gene (TSG) activation and its biological role in oral squamous cell carcinoma (OSCC) remain unknown. Here, we report procaine inhibited DNA methylation by suppressing DNMT activity and increased the expression of PAX9, a differentiation gene in OSCC cells. Interestingly, the reactivation of PAX9 by procaine found to inhibit cell growth and trigger apoptosis in OSCC in vitro and in vivo. Likely, the enhanced PAX9 expression after exposure to procaine controls stemness and differentiation through the autophagy-dependent pathway in OSCC cells. PAX9 inhibition abrogated procaine-induced apoptosis, autophagy, and inhibition of stemness. In OSCC cells, procaine improved anticancer drug sensitivity through PAX9, and its deficiency significantly blunted the anticancer drug sensitivity mediated by procaine. Additionally, NRF2 activation by procaine facilitated the antitumor response of PAX9, and pharmacological inhibition of NRF2 by ML385 reduced death and prevented the decrease in the orosphere-forming potential of OSCC cells. Furthermore, procaine promoted antitumor activity in FaDu xenografts in athymic nude mice, and immunohistochemistry data showed that PAX9 expression was significantly enhanced in the procaine group compared to the vehicle control. In conclusion, PAX9 reactivation in response to DNMT inhibition could trigger a potent antitumor mechanism to provide a new therapeutic strategy for OSCC. [Display omitted] • Inhibition of DNA methyltransferase increases PAX9 expression in OSCC. • Procaine-mediated activation of PAX9 triggers apoptosis and autophagy in OSCC. • Procaine inhibits stemness and induces differentiation is PAX9-dependent in OSCC. • NRF2 activation by procaine facilitates PAX9-mediated antitumor activity. • PAX9 reactivation enhances chemotherapeutics sensitivity in OSCC. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are distinct subpopulations of cancer cells with stem cell-like abilities and are more resilient to chemotherapy, causing tumor relapse. Mitophagy, a selective form of autophagy, removes damaged unwanted mitochondria from cells through a lysosome-based degradation pathway to maintain cellular homeostasis. CSCs use mitophagy as a chief survival response mechanism for their growth, propagation, and tumorigenic ability. Mitochondrial biogenesis is a crucial cellular event replacing damaged mitochondria through the coordinated regulation of several transcription factors to achieve the bioenergetic demands of the cell. Because of the high mitochondrial content in CSCs, mitochondrial biogenesis is an interesting target to address the resistance mechanisms of anti-CSC therapy. However, to what extent both mitophagy and mitochondrial biogenesis are vital in promoting stemness, metabolic reprogramming, and drug resistance in CSCs has yet to be established. Therefore, in this review, we focus on understanding the interesting aspects of mitochondrial rewiring that involve mitophagy and mitochondrial biogenesis in CSCs. We also discuss their coordinated regulation in the elimination of CSCs, with respect to stemness and differentiation of the CSC phenotype, and the different aspects of tumorigenesis such as cancer initiation, progression, resistance, and tumor relapse. Finally, we address several other unanswered questions relating to targeted anti-CSC cancer therapy, which improves patient survival. [ABSTRACT FROM AUTHOR]