Mitophagy is a selective degradation of mitochondria. It has been reported that mitophagy plays a regulatory role in apoptosis and maintaining cell health because it triggers mitochondria turnover and inhibits dysfunctional mitochondria accumulation that can cause cellular degeneration. Mitophagy is regulated by PINK1 protein and parkin. For the selection and disposal of impaired mitochondria, mitophagy also has a role in regulating the number of mitochondria to alter cellular metabolic needs, for mitochondrial steady-state turnover, and during phases of cellular development, such as during cell differentiation. Mitophagy can also regulate energy metabolism in the body until a certain limit and reduces damage caused by external stimuli, thereby protecting the human body from abnormal conditions.[9]
Autophagy is a conserved intracellular degradation system that uses lysosomes to break down cytoplasmic components, contributing significantly to cellular homeostasis by recycling biomolecules and organelles. Its relationship with cancer is intricate and dual-faceted, acting both as a promoter and a suppressor depending on the specific stage and type of cancer involved. It transports substrates to lysosomes through various mechanisms. The most prevalent form of autophagy is macroautophagic (often just called autophagy), which involves the creation of new autophagosomes to deliver materials to lysosomes.[10]
The most distinctive characteristic of autophagy is its ability to degrade nearly all cytoplasm components, including biomolecules such as proteins, nucleic acids, and lipids, as well as various organelles and invading microbes. This degradation process is often selective, making autophagy a crucial mechanism for maintaining cellular homeostasis. It recycles macromolecule precursors to provide nutrients and building blocks, thereby supporting cell survival. However, uncontrolled and persistent activation of autophagy can lead to cellular disintegration and, ultimately, cell death. Dysregulation of autophagy has been linked to various diseases, including neurodegenerative disorders, infectious diseases, and cancers such as liver, colorectal, gastric, breast, and ovarian malignancies.[10]
Under normal conditions and in the early stages of cancer, autophagy acts as a protective mechanism, shielding cells from harmful stimuli and preventing malignant transformation. By mitigating the damaging effects of reactive oxygen species (ROS), autophagy helps prevent DNA damage and maintains genome integrity. During periods of starvation, the production of ROS triggers autophagy. Specifically, hydrogen peroxide (H2O2) reversibly modifies the cysteine residues of ATG4, disrupting the active site necessary for the delipidation of LC3.[14]
Apoptosis, or programmed cell death, is a vital mechanism in biology, essential for developmental sculpturing, tissue homeostasis, and eliminating unwanted cells. Mitochondria play a critical role in regulating this process. Calcium ions (Ca2+) have long been recognized as participants in apoptotic pathways, with mitochondria acting as critical regulators and synchronizers of Ca2 + signalling. Excessive Ca2 + accumulation within mitochondria can trigger apoptosis. The dynamics of Ca2 + between the endoplasmic reticulum (ER) and mitochondria are influenced by the Bcl-2 family proteins, which are pivotal in apoptosis. The number and shape of mitochondria are tightly controlled through processes like mitochondrial fusion and fission, mediated by various mitochondrial-shaping proteins. During apoptotic cell death, mitochondrial fission is observed and appears crucial for advancing the apoptotic pathway.[11]
Apoptotic cell death inhibits oncogenesis at various stages, from initial transformation to metastasis. Cell death also serves as a critical component of cancer treatment, acting as the primary mechanism of action for many anticancer therapies. Most stimuli induce apoptosis through the mitochondrial pathway, where the defining event is mitochondrial outer membrane permeabilization (MOMP). Most approaches inducing mitochondrial outer membrane permeabilization (MOMP) in cancer treatment focus on inhibiting anti-apoptotic BCL-2 proteins. The rationale behind this strategy is that blocking BCL-2 function should either directly initiate apoptosis or enhance sensitivity to other pro-apoptotic therapies. Cancer cells often evade apoptosis by upregulating anti-apoptotic BCL-2 proteins, thereby preventing mitochondrial outer membrane permeabilization (MOMP). The BCL-2 gene was initially identified at a chromosomal translocation breakpoint, placing it under immunoglobulin heavy chain enhancer control, leading to constitutively high BCL-2 expression. While BCL-2 expression alone is not oncogenic, it significantly enhances tumour onset when combined with growth-promoting oncogenes. Numerous studies have confirmed that upregulation of anti-apoptotic BCL-2 proteins is a common feature in various cancers, facilitated by mechanisms like copy number amplification, oncogenic signaling-driven transcriptional upregulation, or suppression of microRNAs that inhibit BCL-2 expression.[12]
Cancer cells also circumvent apoptosis initiation mechanisms. For instance, many cancers exhibit loss of function mutations in the p53 tumour suppressor, which usually induces apoptosis via upregulation of BH3-only proteins such as PUMA in response to DNA damage. Consequently, loss of p53 function can disable DNA damage-induced apoptosis in specific cell types. However, therapies like chemotherapy or radiotherapy can trigger apoptosis independently of p53 through DNA damage.[12]
Cancer is defined by the abnormal and uncontrolled proliferation of cells, which can invade tissues and disrupt normal physiological functions, potentially becoming life-threatening if untreated. The causes of cancer can stem from genetic mutations or environmental factors such as smoking, physical inactivity, and nutritional imbalances. Vitamin D is a pivotal nutrient involved in numerous biochemical pathways and is crucial to overall health. It is particularly significant in various disease processes. Vitamin D is essential not only in preventing malignancies but also as a complementary approach to cancer treatment. It exerts its effects through direct and indirect biochemical mechanisms, contributing to its therapeutic potential in cancer management.[13]
Vitamin D exists in two forms: Vitamin D2, derived from UV irradiation of yeast sterol ergosterol and naturally found in sun-exposed mushrooms, and Vitamin D3, synthesized in the skin and abundant in oil-rich fish like salmon, mackerel, and herring. Commercially available Vitamin D3 is typically derived from 7-dehydrocholesterol, naturally present in the skin or obtained from lanolin. Both forms are used in food fortification and supplements.[14]
After ingestion, Vitamin D (D2 or D3) is absorbed into chylomicrons, entering the lymphatic system and the bloodstream. Initially biologically inert, Vitamin D undergoes hydroxylation in the liver by vitamin D-25-hydroxylase (25-OHase) to form 25(OH)D. Subsequent hydroxylation in the kidneys by 25(OH)D-1α-hydroxylase (CYP27B1) converts it to the biologically active form, 1,25-dihydroxyvitamin D (1,25(OH)2D). This active form interacts with vitamin D receptors in various tissues, including the small intestine and kidneys, significantly stimulating calcium absorption and enhancing dietary calcium and phosphorus absorption efficiency. In osteoblasts, 1,25(OH)2D induces receptor activator of nuclear factor κB ligand (RANKL) expression, which promotes the maturation of osteoclasts that resorb bone matrix and release calcium and minerals into the bloodstream. In the kidneys, 1,25(OH)2D enhances calcium reabsorption from the urine.[14]
The vitamin D receptor is widespread throughout the body, influencing many biological processes. 1,25(OH)2D inhibits cellular proliferation, promotes terminal differentiation, inhibits angiogenesis, stimulates insulin production, suppresses renin production, and enhances macrophage cathelicidin production. Additionally, it promotes its degradation by upregulating 25-hydroxyvitamin D-24-hydroxylase (CYP24A1), converting 25(OH)D and 1,25(OH)2D into water-soluble inactive forms. Various tissues and cells possess 1α-hydroxylase activity, allowing for local production of 1,25(OH)2D, which regulates numerous genes, contributing to the diverse health benefits associated with vitamin D.[14] This study shows a significant increase in the autophagy biomarker levels of p62 and LC3b2. Lc3b1 and the mitochondrial function biomarkers TOM20 and COX4 were significantly reduced.
Theoretically, LC3b2 remains associated with the autophagosome until the fusion of the autophagosome with the lysosome occurs. After that, LC3b2 trapped inside the autophagosome will be degraded. No single marker can likely be used as the only assay to monitor autophagy in ca cx cells.[15, 16]
The correlation between TOM20 and COX4 post-radiation tends to be moderate-positive. This suggests that radiotherapy increased the concentrations of TOM20 and COX4, indicating the degradation of these mitochondrial surface proteins as a result of radiation and treatment. The role of cholecalciferol in cancer prevention and treatment has been observed in epidemiological and preclinical studies, with various mechanisms proposed to explain its anticancer effects. Collected data suggest that cholecalciferol can regulate the entire process of tumorigenesis, from initiation to metastasis and cell-microenvironment interactions. These mechanisms include regulating cell behaviours such as proliferation, differentiation, apoptosis, autophagy, and epithelial-mesenchymal transition (EMT), as well as modulating cell-microenvironment interactions like angiogenesis, antioxidation, inflammation, and the immune system.[16]
Maintaining a balance between mitophagy and mitochondrial production is crucial for cellular health. Targeting autophagy in cancer therapy is a highly intriguing strategy. A deeper understanding of how particular cancer entities can suppress autophagic mechanisms to support cancer survival and evade death could potentially reverse cancer progression. Thus, timing is crucial, given autophagy's controversial role in cancer development. Treatments targeting this mechanism must be administered precisely in the right place and time to be beneficial; otherwise, they may cause unintended harm. Despite positive outcomes from autophagy modulators, the complex nature of autophagy modulation suggests that autophagy itself may not be a critical target and might not be the best standalone approach to alter tumor evolution due to its paradoxical role unless its exact mechanisms are fully elucidated. The molecular mechanisms of autophagy remain an area for further discovery. Whether targeting autophagic mechanisms in cancer is a good approach or potentially a double-edged sword remains an open question. However, suppressing autophagic mechanisms could potentially reverse cancer progression.
