CLU (clusterin) and PPARGC1A/PGC1α coordinately control mitophagy and mitochondrial biogenesis for oral cancer cell survival.

Mitophagy involves the selective elimination of defective mitochondria during chemotherapeutic stress to maintain mitochondrial homeostasis and sustain cancer growth. Here, we showed that CLU (clusterin) is localized to mitochondria to induce mitophagy controlling mitochondrial damage in oral cancer cells. Moreover, overexpression and knockdown of CLU establish its mitophagy-specific role, where CLU acts as an adaptor protein that coordinately interacts with BAX and LC3 recruiting autophagic machinery around damaged mitochondria in response to cisplatin treatment. Interestingly, CLU triggers class III phosphatidylinositol 3-kinase (PtdIns3K) activity around damaged mitochondria, and inhibition of mitophagic flux causes the accumulation of excessive mitophagosomes resulting in reactive oxygen species (ROS)-dependent apoptosis during cisplatin treatment in oral cancer cells. In parallel, we determined that PPARGC1A/PGC1α (PPARG coactivator 1 alpha) activates mitochondrial biogenesis during CLU-induced mitophagy to maintain the mitochondrial pool. Intriguingly, PPARGC1A inhibition through small interfering RNA (siPPARGC1A) and pharmacological inhibitor (SR-18292) treatment counteracts CLU-dependent cytoprotection leading to mitophagy-associated cell death. Furthermore, co-treatment of SR-18292 with cisplatin synergistically suppresses tumor growth in oral cancer xenograft models. In conclusion, CLU and PPARGC1A are essential for sustained cancer cell growth by activating mitophagy and mitochondrial biogenesis, respectively, and their inhibition could provide better therapeutic benefits against oral cancer.

SIRT1 inhibits mitochondrial hyperfusion associated mito-bulb formation to sensitize oral cancer cells for apoptosis in a mtROS-dependent signalling pathway.

SIRT1 (NAD-dependent protein deacetylase sirtuin-1), a class III histone deacetylase acting as a tumor suppressor gene, is downregulated in oral cancer cells. Non-apoptotic doses of cisplatin (CDDP) downregulate SIRT1 expression advocating the mechanism of drug resistance. SIRT1 downregulation orchestrates inhibition of DNM1L-mediated mitochondrial fission, subsequently leading to the formation of hyperfused mitochondrial networks. The hyperfused mitochondrial networks preserve the release of cytochrome C (CYCS) by stabilizing the mitochondrial inner membrane cristae (formation of mitochondrial nucleoid clustering mimicking mito-bulb like structures) and reducing the generation of mitochondrial superoxide to inhibit apoptosis. Overexpression of SIRT1 reverses the mitochondrial hyperfusion by initiating DNM1L-regulated mitochondrial fission. In the overexpressed cells, inhibition of mitochondrial hyperfusion and nucleoid clustering (mito-bulbs) facilitates the cytoplasmic release of CYCS along with an enhanced generation of mitochondrial superoxide for the subsequent induction of apoptosis. Further, low-dose priming with gallic acid (GA), a bio-active SIRT1 activator, nullifies CDDP-mediated apoptosis inhibition by suppressing mitochondrial hyperfusion. In this setting, SIRT1 knockdown hinders apoptosis activation in GA-primed oral cancer cells. Similarly, SIRT1 overexpression in the CDDP resistance oral cancer-derived polyploid giant cancer cells (PGCCs) re-sensitizes the cells to apoptosis. Interestingly, synergistically treated with CDDP, GA induces apoptosis in the PGCCs by inhibiting mitochondrial hyperfusion.

Near-Infrared-Induced NO-Releasing Photothermal Adhesive Hydrogel with Enhanced Antibacterial Properties.

Bacterial infection and the development of antibiotic-resistant bacteria have decreased the effectiveness of traditional antibiotic treatments for wound healing. The design of a multifunctional adhesive hydrogel with antibacterial activity, self-healing properties, and on-demand removability to promote wound healing is highly desirable. In this work, a photothermal cyclodextrin with a NO-releasing moiety has been incorporated within an oxidized sodium alginate conjugated polyacrylamide (OS@PA) hydrogel to get a photothermal NO-releasing GSNOCD-OS@PA hydrogel. Such a multifunctional hydrogel has the unique feature of combined antibacterial activity as a result of a controlled photothermal effect and NO gas release under an 808 near-infrared laser. Because of oxidized sodium alginate (OSA), the hydrogel matrix easily adheres to the skin under twisted and bent states. In vitro cytotoxicity analysis against 3T3 cells showed that the hydrogels OS@PA and GSNOCD-OS@PA are noncytotoxic under laser exposure. The temperature-induced NO release by GSNOCD-OS@PA reached 31.7 mg/L when irradiated with an 808 nm laser for 10 min. The combined photothermal therapy and NO release from GSNOCD-OS@PA effectively reduced viability of both Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) to 3 and 5%, respectively. Importantly, the phototherapeutic NO-releasing platform displayed effective fibroblast proliferation in a cell scratch assay.

Co-targeting autophagy and NRF2 signaling triggers mitochondrial superoxide to sensitize oral cancer stem cells for cisplatin-induced apoptosis.

Cancer stem cell (CSC) populations are regulated by autophagy, which in turn modulates tumorigenicity and malignancy. In this study, we demonstrated that cisplatin treatment enriches the CSCs population by increasing autophagosome formation and speeding up autophagosome-lysosome fusion by recruiting RAB7 to autolysosomes. Further, cisplatin treatment stimulates lysosomal activity and increases autophagic flux in oral CD44+ cells. Interestingly, both ATG5- and BECN1-dependent autophagy are essential for maintaining cancer stemness, self-renewal, and resistance to cisplatin-induced cytotoxicity in oral CD44+ cells. Moreover, we discovered that autophagy-deficient (shATG5 and/or shBECN1) CD44+ cells activates nuclear factor, erythroid 2 like 2 (NRF2) signaling, which in turn reduces the elevated reactive oxygen species (ROS) level enhancing cancer stemness. Genetic inhibition of NRF2 (siNRF2) in autophagy-deficient CD44+ cells increases mitochondrial ROS (mtROS) level, reducing cisplatin-resistance CSCs, and pre-treatment with mitoTEMPO [a mitochondria-targeted superoxide dismutase (SOD) mimetic] lessened the cytotoxic effect enhancing cancer stemness. We also found that inhibiting autophagy (with CQ) and NRF2 signaling (with ML-385) combinedly increases cisplatin cytotoxicity, thereby suppressing the expansion of oral CD44+ cells; this finding has the potential to be clinically applicable in resolving CSC-associated chemoresistance and tumor relapse in oral cancer.

Targeting SIRT1-regulated autophagic cell death as a novel therapeutic avenue for cancer prevention.

Cellular localization and deacetylation activity of sirtuin 1 (SIRT1) has a significant role in cancer regulation. The multifactorial role of SIRT1 in autophagy regulates several cancer-associated cellular phenotypes, aiding cellular survival and cell death induction. SIRT1-mediated deacetylation of autophagy-related genes (ATGs) and associated signaling mediators control carcinogenesis. The hyperactivation of bulk autophagy, disrupted lysosomal and mitochondrial biogenesis, and excessive mitophagy are key mechanism for SIRT1-mediated autophagic cell death (ACD). In terms of the SIRT1-ACD nexus, identifying SIRT1-activating small molecules and understanding the possible mechanism triggering ACD could be a potential therapeutic avenue for cancer prevention. In this review, we provide an update on the structural and functional intricacy of SIRT1 and SIRT1-mediated autophagy activation as an alternative cell death modality for cancer prevention.

Inflammasomes in cancer: Effect of epigenetic and autophagic modulations.

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-1ß 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.

Mitochondrial dysfunction as a driver of NLRP3 inflammasome activation and its modulation through mitophagy for potential therapeutics.

The NLR family pyrin domain containing 3 (NLRP3) inflammasome is responsible for the sensation of various pathogenic and non-pathogenic damage signals and has a vital role in neuroinflammation and neural diseases. Various stimuli, such as microbial infection, misfolded protein aggregates, and aberrant deposition of proteins can induce NLRP3 inflammasome in neural cells. Once triggered, the NLRP3 inflammasome leads to the activation of caspase-1, which in turn activates inflammatory cytokines, such as interleukin-1ß and interleukin -18, and induces pyroptotic cell death. Mitochondria are critically involved in diverse cellular processes and are involved in regulating cellular redox status, calcium levels, inflammasome activation, and cell death. Mitochondrial dysfunction and subsequent accumulation of mitochondrial reactive oxygen species, mitochondrial deoxyribonucleic acid, and other mitochondria-associated proteins and lipids play vital roles in the instigation of the NLRP3 inflammasome. In addition, the processes of mitochondrial dynamics, such as fission and fusion, are essential in the maintenance of mitochondrial integrity and their imbalance also promotes NLRP3 inflammasome activation. In this connection, mitophagy-mediated maintenance of mitochondrial homeostasis restricts NLRP3 inflammasome hyperactivation and its consequences in various neurological disorders. Hence, mitophagy can be exploited as a potential strategy to target damaged mitochondria induced NLRP3 inflammasome activation and its lethal consequences. Therefore, the identification of novel mitophagy modulators has promising therapeutic potential for NLRP3 inflammasome-associated neuronal diseases.

Intricate role of mitochondrial calcium signalling in mitochondrial quality control for regulation of cancer cell fate.

Mitochondrial quality control is crucial for sustaining cellular maintenance. Mitochondrial Ca2+ plays an important role in the maintenance of mitochondrial quality control through regulation of mitochondrial dynamics, mitophagy and mitochondrial biogenesis for preserving cellular homeostasis. The regulation of this dynamic interlink between these mitochondrial networks and mitochondrial Ca2+ appears indispensable for the adaptation of cells under external stimuli. Moreover, dysregulation of mitochondrial Ca2+ divulges impaired mitochondrial control that results in several pathological conditions such as cancer. Hence this review untangles the interplay between mitochondrial Ca2+ and quality control that govern mitochondrial health and mitochondrial coordinates in the development of cancer.

Mitochondrial rewiring through mitophagy and mitochondrial biogenesis in cancer stem cells: A potential target for anti-CSC cancer therapy.

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.