The Interplay between Autophagy and Mitochondria in Cancer
Abstract
:1. Introduction: The Function of Mitochondria
2. Autophagy
2.1. Selective Autophagy—Mitophagy
2.1.1. Ubiquitin-Mediated Mitophagy
2.1.2. Ubiquitin-Independent Mitophagy
Type of Mitophagy Receptors | Key Properties | Regulators (Positive [+]/Negative [-]) | Ubiquitin Dependent (+/-) | Location |
---|---|---|---|---|
Protein receptors | ||||
SQSTM/p62 | Oxidative-stress-inducible protein; regulator of Nrf2 factor, NF-kB [33] | ULK1 [+]; CK2 [+]; TBK1 [+]; mTORC1 [+]; | + | Cytoplasm |
CALCOCO2/NDP52 | Promotor of phagophore biogenesis [34] | TANK binding kinase 1 (TBK1), [+]; | + | Cytoplasm |
OPTN (Optineurin) | Promotor of phagophore biogenesis [35] | TNF-α [+]; Interferons [+]; | + | Cytoplasm |
NBR1 | Oxidative-stress-inducible protein; cooperates with p62 [35]; | - | + | Cytoplasm |
TAX1BP1 | Eliminator of excessive ROS [36,37] | - | + | Cytoplasm |
BNIP3 | BCL2 apoptosis regulator protein (pro-apoptotic); promotes hypoxia-induced autophagy; regulator of mTOR [32]; | FOXO3 (starvation, [+]); HIF-1 [+]; MA-5 [+]; | -/+ | OMM |
BNIP3L/NIX | Stress sensor; inducer of cell death and mitophagy (ischemia, erythrocyte development [38]) | HIF1A (hypoxia, [+]); GTPase RHEB (phosphorylation, [+]); PKA (phosphorylation, [-]); | -/+ | OMM |
FUNDC1 | Involved in hypoxia-induced mitophagy; dephosphorylated form activates fission and mitophagy; connects with fission (DNM1L, DRP1)/fusion (OPA1) proteins; regulator of proteostasis [39] | SRC (kinase, [-]); CK2 (kinase, [-]); ULK1(kinase, [+]); PGAM5 (phosphatase, [+]); MARCH5 (ubiquitin ligase E3, [-]); MIR137 [-]; | - | OMM |
BCL2L13 | Promotor of mitochondrial fragmentation; regulator of fission; maintainer of mitochondrial quality; inducer of apoptosis [32,40] | Unknown; | - | OMM |
FKBP8 | Anti-apoptotic protein; regulator of mTORC1; exerts peptidylprolyl isomerase activity [32,41] | RHEB [-]; | - | OMM |
AMBRA1 | Phagophore activator; along with BECN1, it is an activator of PtdIns3k (phosphatidylinositol 3-kinase); interacts with HUWE1 (E3 ubiquitin ligase) and thus induces ubiquitin-independent mitophagy [32,42] | NFKBI [+]; BCL2 family proteins [-]; MCL1 [-]; CHUK [+]; GSK3B [+]; | -/+ | OMM |
PHB2 (prohibitin 2) | Regulator of mitochondrial proteases; maintainer of mitochondrial genome; promotor of PINK1-PARKIN-dependent mitophagy; along with AURKA, it is a kinase promotor of PARKIN-independent mitophagy [32] | AURKA [+] | -/+ | OMM/IMM |
Lipid receptors | ||||
CL (cardiolipin) | Maintainer of electron transport chain function; involved in apoptosis; cooperates with BECN1 (mitophagy) and DNM1L (mitochondrial division) [43] | CRLS1 (cardiolipin synthase 1, [+]); PLSCR3 ((phospholipid scramblase 3), transport CL to OMM [+]); NDPK-D (kinase, [+]) PRRT2/PKC [+]; SNCA[+]; | - | OMM/IMM |
Ceramide | Ceramide-induced mitophagy [32] | CERS1(ceramide synthase 1, [+]); DNM1L [+]; | - | OMM |
2.1.3. Chaperone-Mediated Autophagy
3. Role of Autophagy in Tumorigenesis
4. Modulation of Mitochondria and Autophagy Exhibits Promise in Cancer Treatment
Compound | Mechanism | Ref. |
---|---|---|
Mitochondria inhibitors | ||
Rotenone | Inhibits complex I in gastric cancer cells (MKN-1, MKN-B, and MKN-74) | [91] |
BAY 87-2243 | Inhibited complex I in melanoma tumor xenograft (SK-MEL-28 and G-361 cells) and in vitro (A-375, G-361, SK-MEL-5, SK-MEL-28 cells) | [92] |
MitoVES (mitochondrially targeted vitamin E succinate) | Inhibits complex II in colon cancer (HCT116 cells in vitro and in BALB/c nu/nu mice) | [93] |
Atovaquone (ATO) | Inhibits complex III in breast cancer cells (MCF7) | [94] |
Antimycin A | Inhibits complex III in acute myeloid leukemia U937 and HL-60 cells | [95] |
VLX600 | Acts as an OXPHOS inhibitor (inhibiting complexes I, II, IV) in colon cancer 3-D microtissues; Acts as an iron chelator; Induces autophagy-dependent cell death and mitophagy through BNIP3/BNIP3L activation in glioblastoma cells (U251, MZ54, NCH644) and organotypic brain slice cultures | [96] |
BTB06584 | Inhibits ATP synthase in non-small-cell lung cancer cells (A549) | [97] |
Oligomycin | Inhibits ATP synthase in breast metastasis cells (MDA-MB-231) | [98] |
Mitochondrial activators | ||
Ophinobolin A (OPA) | Activates complex IV in lung squamous cell carcinoma (NCI-H1703) | [70] |
Autophagy inhibitors | ||
Vitexin | Inhibits LC3-associated autophagosome formation Decreases p-ERK1/2 levels in hepatocellular carcinoma (SK-Hep1 and Hepa1-6 cells) | [99] |
RA-XII | Inhibits AMPK pathway; Induces apoptosis through the suppression of autophagy in liver cancer (HepG2 cells); | [100] |
3-methyladenine (3-MA) | Inhibits LC3-I/II and class III PI3K complex; Increases p62 levels in colon cancer cells (LOVO and SW480) | [101] |
Astragaloside II | Decreases the levels of LC3-II and Beclin-1 in hepatic cancer cell lines (Bel-7402 and Bel-7402/FU) | [102] |
Bafilomycin A1 | Increases LC3 levels; Promotes the association of Beclin-1 and Bcl-2; Blocks V-ATPase in B-cell acute lymphoblastic leukemia (697 cells) | [103] |
SAR405 | Suppresses VPS34 and PIK3C3 kinase in carcinoma cell line H1299 | [104] |
Clarithromycin | Upregulates LC3-II in primary colorectal cancer surgical samples; Induces autophagosome formation and decreases p62/SQSTM1 levels in colorectal cancer (HCT116 cells) | [105] |
4-acetylantroquinonol B | Inhibits ATG5 in ovarian cell line ES-2 | [106] |
Autophagy activators | ||
Salinomycin | Increases LC3B-II levels and vacuolization in melanoma SK-Mel-19 cells | [107] |
Esomeprazole | Inhibits V-ATPase in lung cancer (A549/Taxol cells) | [108] |
Niraparib | Inhibits AKT/mTOR pathway and increases ROS levels; Activates ERK1/2 and increases LC3-II in hepatocellular carcinoma (Huh7 and HepG2) | [109] |
Matrine | Leads to the accumulation of LC3-II; Reduces the levels of total AKT and mTOR in gastric cancer (SGC-7901) | [110] |
Bisindolylmaleimide (BMA-155Cl) | Increases Beclin-1, NF-kB, and p65 levels in hepatocarcinoma HepG-2 cells | [111] |
Resveratrol Spermidine | Activates SIRT1 in colon cancer HCT 116 cells | [112] |
Bicyclol | Inhibits p-AKT and pERK; Decreases the levels of p-mTOR (Ser2448); Increases LC3-II levels in hepatocellular carcinoma cell HepG2 | [113] |
Glycochenodeoxycholate | Increases LC3-II and pAMPK levels; Decreases p63 and pmTOR levels in hepatocellular carcinoma (SMMC7721 and Huh7 cells) | [114] |
Lapatinib | Increases LC3-II, ATG7, Beclin-1, and ATG5 levels in acute myeloblastic leukemia (U937 cells) | [115] |
Lycorine | Decreases TCRP1 (tongue-cancer-resistance-associated protein 1) and p-AKT levels, increases LC3 II levels, and decreases Beclin-1 levels in hepatocellular carcinoma (HepG2 and SMMC-7721) | [116] |
Baicalein/baicalin | Activates ATG5, ATG7, ATG12, Beclin-1, and LC3-IIB proteins in bladder cancer T24 cells | [117] |
Epigallocatechin gallate (EGCG) | Elevates levels of LC3-II; Increases number of autophagosomes in cepatocellular carcinoma cell line HepG2 | [118] |
Title | Drug | Target | Cancer Type | ClinicalTrials.gov ID | Ref. |
---|---|---|---|---|---|
Targeted apoptotic pathway | |||||
A Phase I clinical trial evaluating the tolerance and pharmacokinetics of TQB3909 tablets in patients with relapsed or refractory advanced malignant tumors (China) | TQB3909 | BCL-2 inhibitor | Phase I: advanced malignant tumors | NCT04975204 | [119] |
A Phase Ib/ii study to investigate the safety, tolerance and pharmacokinetics of TQB3909 with HR-positive, HER2-negative advanced breast cancer (China) | Phase Ib/II: advanced breast cancer | NCT05775575 | |||
A Phase Ib/II clinical trial on the safety and efficacy of TQB3909 tablets in patients with recurrent or refractory CLL/SLL (China) | Phase Ib/II: chronic lymphocytic leukemia/small lymphocytic lymphoma | NCT05959694 | |||
A Phase 1a/1b open-label dose escalation and expansion study of Bcl-2 inhibitor BGB-11417 in patients with mature B-cell malignancies (United States) | Sonrotoclax (BGB-11417) or Sontroclax in combination with zanubrutinib and obinutuzumab | BCL-2 inhibitor | Phase Ia/Ib: mature B-cell malignancies | NCT04277637 | [120] |
A Phase I study of venetoclax in combination with cytotoxic chemotherapy, including calaspargase pegol, for children, adolescents and young adults with high-risk hematologic malignancies (United States) | Venetoclax in combination with azacitidine cytarabine, methotrexate, hydrocortisone, leucovorin, dexamethasone, vincristine, doxorubicin, dexrazoxane, calaspargase, pegol, erwinia asparaginase | Acute myeloid leukemia/chronic lymphocytic leukemia Phase I: hematologic malignancies | FDA-approved NCT05292664 | ||
A Phase 1 study of triplet therapy with navitoclax, venetoclax, and decitabine for high-risk myeloid malignancies (United States) | Venetoclax in combination with navitoclax and decitabine | Phase I: myeloid malignancy | NCT05455294 | ||
Phase 1 study of venetoclax, a BCL2 antagonist, for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) (United States) | Venetoclax | Phase I: dendritic cell neoplasm | NCT03485547 | ||
A Phase 1b study of palbociclib, letrozole and venetoclax in ER and BCL-2 positive locally advanced or metastatic breast cancer (Australia) | Venetoclax in combination with palbociclib and letrozole | Phase Ib: breast cancer | NCT03900884 | ||
Phase Ib/II study of enzalutamide with venetoclax (ABT-199) in patients with metastatic castrate resistant prostate cancer (mCRPC) (United States) | Venetoclax in combination with enzalutamide | Phase Ib/II: prostate cancer | NCT03751436 | ||
A Phase 1b study of venetoclax in combination with pembrolizumab in subjects with previously untreated NSCLC whose tumors have high PD-L1 expression (United States) | Venetoclax in combination with pembrolizumab | Phase Ib: non-small-cell lung cancer | |||
A Phase 1 study of oral LOXO-338, a selective BCL-2 inhibitor, in patients with advanced hematologic malignancies (United States) | LOXO-338 | Phase I: advanced hematologic malignancies | NCT05024045 | [121] | |
A Phase 1 study investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of second mitochondrial-derived activator of caspases mimetic BGB-24714 as monotherapy and with combination therapies in patients with solid tumors | BGB-24714 or BGB-24714 in combination with paclitaxel, carboplatin, docetaxel | SMAC (mitochondrial-derived activator of caspases) mimetic and inhibitor of apoptosis protein | Phase I: solid tumors | NCT05381909 | [122] |
A randomized, double-blind placebo-controlled, Phase 3 study of Debio 1143 in combination with platinum-based chemotherapy and standard fractionation intensity-modulated radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck, suitable for definitive chemoradiotherapy (TrilynX) (United States) | Xevinapant (Debio 1143) in combination with chemotherapy | Second mitochondrial-derived activator of caspases | Phase III: advanced squamous cell carcinoma of the head and neck | NCT04459715 | [123] |
A Phase 1b study of the OxPhos inhibitor ME-344 combined with bevacizumab in previously treated metastatic colorectal cancer (United States) | Me-344 combined with bevacizumab | OxPhos pathway inhibitor; purine biosynthesis inhibitor | Phase Ib: previously treated metastatic colorectal cancer | NCT05824559 | [124] |
A Phase 1 open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of Minnelide™ capsules given alone or in combination with paclitaxel in patients with advanced gastric cancer (Republic of Korea) | Minnelide (triptolide) | SIRT3 regulator; c-myc down-regulator | Phase I: gastric cancer | NCT05566834 | [125] |
A Phase II trial of the superenhancer inhibitor minnelide in advanced refractory adenosquamous carcinoma of the pancreas (ASCP) (United States) | Phase II: advanced refractory adenosquamous carcinoma of the pancreas | NCT04896073 | |||
A Phase 1b open-label, dose-escalation, safety, and pharmacodynamic study of Minnelide™ capsules given in combination with osimertinib in patients with EGFR mutated NSCLC (United States) | Minnelide in combination with osimertinib | Phase Ib: lung cancer | NCT05166616 | ||
A Phase 1b, open-label, safety, pharmacokinetic, and pharmacodynamic study of an anti-super-enhancer Minnelide given along with abraxane plus gemcitabine in patients with metastatic adenocarcinoma of the pancreas (Republic of Korea) | Minnelide in combination with Abraxane and gemcitabine | Phase Ib: metastatic adenocarcinoma of the pancreas | NCT05557851 | ||
A Phase 1, multi-center, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of minnelide™ capsules given alone or in combination with protein-bound paclitaxel in patients with advanced solid tumors (United States) | Minnelide in combination with paclitaxel | Phase I: advanced solid tumors | NCT03129139 | ||
Targeting mitochondrial metabolism | |||||
A Phase I trial targeting mitochondrial metabolism with papaverine in combination with chemoradiation for stage II-III non-small cell lung cancer (United States) | Papaverine in combination with chemoradiation and immunotherapy | Mitochondrial Complex I inhibitor | Phase I: Stage II–III non-small-cell lung cancer | NCT05136846 | [126] |
Phase I trial of phenformin with patients with combination BRAF inhibitor/MEK inhibitor in patients with BRAFV600E/K-mutated melanoma (United States) | Phenformin in combination with dabrafenib and phenformin | Mitochondrial complex I inhibitor | Phase I: melanoma | NCT03026517 | [68] |
Phase II clinical trial repurposing atovaquone for the treatment of platinum-resistant ovarian cancer (United States) | Atovaquone (Mepron) | Mitochondrial complex III inhibitor | Phase II: ovarian cancer | NCT05998135 | [127] |
A Trial of atovaquone (Mepron®) combined with conventional chemotherapy for de novo acute myeloid leukemia (AML) adolescents, and young adults (ATACC AML) (United States) | Atovaquone in combination with conventional chemotherapy (cytarabine, daunorubicin, etoposide, gemtuzumab ozogamicin) | Mitochondrial complex III inhibitor | Phase I: acute myeloid leukemia | NCT03568994 | |
A Phase I study of oral carboxyamidotriazole orotate (CTO) titrated as a single agent in patients with advanced or metastatic solid tumors and titrated in combination therapy with temodar® for patients with glioblastoma and other recurrent malignant gliomas or in combination with temodar® and radiation therapy for patients with newly diagnosed glioblastoma and malignant gliomas (United States) | Carboxyamidotriazole orotate or in combination with temodar/radiation therapy | Non-voltage-dependent calcium channel inhibitor | Phase I: advanced or metastatic solid tumors Phase I: glioblastoma, malignant gliomas | NCT01107522 | [128] |
A Phase II clinical trial of CPI-613 in patients with relapsed or refractory Burkitt lymphoma/leukemia or high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (United States) | Devimistat (CPI-613) | Pyruvate dehydrogenase and α-ketoglutarate dehydrogenase/2-oxoglutarate dehydrogenase | Phase II: relapsed/refractory Burkitt’s Lymphoma/leukemia or high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 | NCT03793140 | [129] |
A Phase II/I open-label clinical trial of CPI-613 in combination with modified FOLFIRINOX in patients with locally advanced pancreatic cancer and good performance status (United States) | Devimistat in combination with modified FOLFIRINOX (oxaliplatin, irinotecan, 5-flurouracil, and folinic acid) | Phase II/I: advanced pancreatic cancer | NCT03699319 | ||
A Phase I dose-escalation study of CPI-613 (Devimistat) in combination with chemoradiation in patients with pancreatic adenocarcinoma (United States) | Devimistat in combination with chemoradiation | Phase I: pancreatic adenocarcinoma | NCT05325281 | ||
Phase II open-label multi-cohort study evaluating CPI-613 (Devimistat) in combination with hydroxychloroquine and 5-fluorouracil or gemcitabine in patients with advanced chemorefractory colorectal, pancreatic, or other solid cancers (United States) | Devimistat in combination with hydroxychloroquine 5-fluorouracil or gemcitabine | Phase II: advanced chemorefractory colorectal, pancreatic or solid tumors | NCT05733000 | ||
Phase II study of AG-120 in people with IDH1 mutant chondrosarcoma (United States) | Ivosidenib (AG-120) | IDH1 inhibitor | Acute myeloid leukemia Phase II: Chondrosarcoma | FDA-approved NCT04278781 | [130] |
A Phase I, multicenter, open-label, dose-escalation and expansion, safety, pharmacokinetic, pharmacodynamic, and clinical activity study of orally administered AG-120 in subjects with advanced hematologic malignancies with an IDH1 mutation (United States) | Phase I: advanced hematologic malignancies | NCT02074839 | |||
Phase Ib/II investigator initiated study of the IDH1-mutant inhibitor ivosidenib (AG120) with the BCL2 inhibitor venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies (United States) | Ivosidenib in combination with venetoclax +/- azacitidine | Phase Ib/II: IDH1-mutated hematologic malignancies | NCT03471260 | ||
Phase II study of enasidenib in IDH2-mutated malignant sinonasal and skull base tumors (United States) | Enasidenib | IDH2 inhibitor | FDA-approved for acute myeloid leukemia Phase II: malignant sinonasal and skull base tumors | NCT06176989 | [131] |
Trial of dichloroacetate (DCA) in glioblastoma multiforme (GBM) (United States) | Dichloracetate | Pyruvate dehydrogenase complex inhibitor | Phase IIA: glioblastoma | NCT05120284 | [132] |
Targeting autophagy | |||||
LIMIT melanoma: (lysosomal inhibition + melanoma immunotherapy) a Phase 1/2 open label trial of nivolumab and hydroxychloroquine or nivolumab/ipilimumab and hydroxychloroquine in patients with advanced melanoma (United States) | Hydroxychloroquine in combination with nivolumab/ipilimumab | Lysosomal acidification inhibitor; Disrupt the fusion of autophagosome with lysosome | Phase I/II: melanoma | NCT04464759 | [81,133] |
THREAD: A Phase I trial of trametinib and hydroxychloroquine in patients with advanced pancreatic cancer (United States) | Hydroxychloroquine in combination with trametinib | Phase I: advanced pancreatic cancer | NCT03825289 | ||
Binimetinib plus hydroxychloroquine in KRAS mutant metastatic pancreatic cancer (United States) | Hydroxychloroquine in combination with binimetinib | Phase I: KRAS mutant metastatic pancreatic cancer | NCT04132505 | ||
Modulation of sorafenib induced autophagy using hydroxychloroquine in hepatocellular cancer (United States) | Hydroxychloroquine in combination with sorafenib | Phase II: advanced hepatocellular cancer | NCT03037437 | ||
A Phase I trial of MK-2206 and hydroxychloroquine in solid tumors, melanoma, renal and prostate cancer to examine the role of autophagy in tumorigenesis (United States) | Hydroxychloroquine in combination with Akt inhibitor MK2206 | Phase I: advanced solid tumors, melanoma, prostate, kidney cancer | NCT01480154 | ||
Treatment of adults with newly diagnosed glioblastoma with partial brain radiation therapy plus temozolomide and chloroquine followed by tumor treating fields plus temozolomide and chloroquine—a pilot study (United States) | Chloroquine in combination with radiotherapy or tumor-treating fields therapy | Phase I: glioblastoma | NCT04397679 | ||
Phase II study of oral metformin for intravesical treatment of non-muscle-invasive bladder cancer (Netherlands) | Metformin | AMPK activator; mTOR inhibitor; STAT3-mediated pathway inhibitor; autophagy inducer (decreases p62, increases LC3-II); Complex I inhibitor | Phase II: non-muscle-invasive bladder cancer | NCT03379909 | [134,135,136] |
STOP-LEUKEMIA: Repurposing metformin as a leukemia-preventive drug in CCUS and LR-MDS (Denmark) | Metformin | Phase II: clonal cytopenia, myelodysplastic neoplasms | NCT04741945 | ||
Clinical effects of metformin on fertility-sparing treatment for early endometrial cancer (Republic of Korea) | Phase III: endometrial cancer | NCT04792749 | |||
Profiling and reversing metabolic insufficiency in the tumor microenvironment in advanced melanoma: a trial of pembrolizumab and metformin versus pembrolizumab alone in advanced melanoma (United States) | Metformin in combination with pembrolizumab | Phase I: advanced melanoma | NCT03311308 | ||
Phase 2A pilot trial of metformin, digoxin, simvastatin (C3) in combination with gemcitabine in subjects with recurrent/refractory metastatic advanced pancreatic cancer) (United States) | Metformin in combination with simvastatin, and digoxin +/- gemcitabine | Phase I/II: metastatic advanced pancreatic cancer | NCT06030622 | ||
Effect of metformin plus tyrosine kinase inhibitors compared with tyrosine kinase inhibitors alone for patients with advanced non-small cell lung cancer and EGFR mutations: Phase 3 randomized clinical trial (Mexico) | Metformin in combination with tyrosine kinase inhibitors | Phase II: advanced non-small-cell lung cancer | NCT05445791 | ||
A Phase 0, single-center, open-label, dose-escalating trial using super-selective intra-arterial infusion of a single dose of temsirolimus for the treatment of recurrent high-grade glioma (United states) | Temsirolimus (CCI-779) | Autophagy in-ducer; mTOR inhibitor | Advanced renal cell carcinoma Early phase 0: glioma, glioblastoma | FDA-approved NCT05773326 | [137] |
Phase II trial of encapsulated rapamycin (eRapa) for bladder cancer prevention (United States) | Rapamycin (Sirolimus) | Autophagy inducer; mTOR inhibitor | Phase II: bladder cancer | NCT04375813 | [138] |
A Phase I trial of sirolimus or everolimus or temsirolimus (mTOR inhibitor) and vorinostat (histone deacetylase inhibitor) in advanced cancer (United States) | Rapamycin in combination with vorinostat | Phase I: advanced cancer | NCT01087554 | ||
Combination of autophagy selective therapeutics (COAST) in advanced solid tumors or relapsed prostate cancer, a Phase I/II Trial (United States) | Rapamycin in combination with hydroxychloroquine, metformin or dasatanib or nelfinavir | Phase I/II: advanced solid tumors, relapsed prostate cancer | NCT05036226 | ||
Everolimus (afinitor) | Autophagy in-ducer; mTOR inhibitor | HER2-negative advanced breast cancer, pancreatic neuroendocrine tumors, renal cell carcinoma, angiomyolipoma | FDA-approved | [139,140] | |
Efficacy and safety of epigallocatechin-3-gallate, an important polyphenolic that originates from tea, in patients with esophageal squamous cancer: a Phase II trial (China) | Epigallocatechin gallate (EGCG) | Autophagy activator through ROS elevation, Beclin-1- and LC3B-increasing | Phase II: esophageal squamous cancer | NCT06398405 | [87] |
5. Challenges Faced in Relation to Therapies Targeting Mitochondrial and Autophagic Processes
6. Autophagy-Related Genes Hold Potential as Prognostic and Diagnostic Biomarkers for Cancer
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
13OD | 13-oxyingenol-dodecanoate |
ACD | autophagic cell death |
AJCC | American Joint Committee on Cancer |
AKT1 | AKT serine/threonine kinase 1 |
AMBRA1 | the activating molecule in BECLIN1-regulated autophagy 1 |
AMPK | AMP-activated protein kinase |
ATP | adenosine triphosphate |
ATP5F1A | ATP synthase F1 subunit alpha |
BAG1 | Bcl2-associated athanogene 1 protein |
BCL-2 | B-cell lymphoma-2 |
BCL2L13 | BCL2-Like 13 |
Beclin1 | Bcl-2-interacting myosin-like coiled-coil |
BIF1 | Bax-interacting factor 1 |
BMAL1 | basic helix–loop–helix ARNT-like 1 |
BNIP3 | BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 |
CALCOCO2/NDP52 | calcium-binding and coiled-coil domain 2 |
CAT | catalase |
CHIP | carboxyl terminus of hsc70-interacting protein |
CHMP2 | charged multivesicular body protein 2 |
CL | cardiolipin |
CLEAR | coordinated lysosomal expression and regulation |
CMA | chaperone-mediated autophagy |
COX IV | cytochrome c oxidase subunit 4 |
DAPK | death-associated protein kinase |
DAPK | death-associated protein kinase |
DJ-1 | nucleic acid deglycase |
DNAJB1 | DnaJ heat shock protein family (Hsp40) member B1 |
DRAM | damage-regulated autophagy modulator |
DUB | deubiquitinase |
DYNC1LI2 | Dynein Cytoplasmic 1 Light Intermediate Chain 2 |
EF1α | elongation factor 1-α |
EGCG | epigallocatechin gallate |
ER | endoplasmic reticulum |
ESCRT | endosomal sorting complex required for transport |
ETC | electron transport chain |
FKBP8 | FKBP Prolyl Isomerase 8 |
FUNDC1 | FUN14 Domain-Containing 1 |
GABARAP | GABA type A receptor-associated protein |
GFAP | glial fibrillary acidic protein |
GP78 | glycoprotein 78 |
GSH | glutathione |
GSH-Px | glutathione peroxidase |
GTEx | genotype-tissue expression |
GTP | guanosine triphosphate |
HMT | horizontal mitochondrial transfer |
HOP | hsp70-hsp90 organizing protein |
HOPS | homotypic fusion and protein sorting |
Hsp40 | heat shock protein 40 |
Hsp70 | heat shock protein 70 |
IMM | inner mitochondrial membrane |
KGDH | α-ketoglutarate dehydrogenase |
LAMP-2A | lysosome-associated membrane protein type 2A |
LC3 | microtubule-associated protein 1 light chain 3 |
LIR | LC3-interacting region |
MAM | mitochondria-associated membrane |
MAP1LC3/LC3 | microtubule associated protein 1 light chain 3 |
MFN2 | Mitofusin-2 |
Miro | mitochondrial Rho GTPase |
MMP | mitochondrial membrane potential |
MTCH1 | mitochondrial carrier 1 |
mTORC1 | mechanistic target of rapamycin complex 1 |
mTORC2 | mammalian target of rapamycin complex 2 |
mtROS | mitochondrial reactive oxygen species |
MUL1 | mitochondrial E3 ubiquitin ligase 1 |
NBR1 | neighbor of BRCA1 gene 1 protein |
NFAT1 | nuclear factor of activated T cells |
NFE2L2 | NFE2 Like BZIP transcription factor 2 |
NF-kB | nuclear factor kappa-light-chain-enhancer of activated B cells |
NOX | NADPH oxidase |
Nrf2 | nuclear factor erythroid 2-related factor 2 |
OMM | outer mitochondrial membrane |
OPTN | optineurin |
OSCC | oral squamous cell carcinoma |
OXPHOS | oxidative phosphorylation |
PAS | pre-autophagosomal structure |
PDH | pyruvate dehydrogenase |
PE | phosphatidylethanolamine |
PER1/2 | period circadian protein homolog 1/2 |
PGAM5 | mitochondrial serine/threonine protein phosphatase |
PHB2 | prohibitin 2 |
PHLPP1 | PH Domain And Leucine Rich Repeat Protein Phosphatase 1 |
PI3K | phosphatidylinositol 3-kinase |
PI3P | phosphoinositide 3-phosphate |
PINK1 | PTEN-induced putative kinase 1 |
PLEKHM1 | pleckstrin homology domain-containing family M member 1 |
PPT1 | palmitoyl-protein thioesterase 1 |
PTEN | phosphatase and tensin homolog |
Rab-7A | Ras-related protein Rab-7A |
RARα | retinoic acid receptor alpha |
RHOT1 | Ras homolog family member T1 |
RILP | Rab-interacting lysosomal protein |
ROS | reactive oxygen species |
SIAH1 | seven in absentia homolog 1 |
SMAC | mitochondrial-derived activator of caspases |
SNARE | soluble N-ethylmaleimide-sensitive attachment protein receptors |
SOD | superoxide dismutase |
SQSTM1/p62 | sequestosome 1 |
TAX1BP1 | Tax1 binding protein 1 |
TBK1 | TANK binding kinase 1 |
TCA | tricarboxylic acid |
TCGA | The Cancer Genome Atlas |
TFEB | transcription factor EB |
TLR | toll-like receptor |
TNFa | tumor necrosis factor α |
Tom20 | mitochondrial import receptor subunit TOM20 homolog |
TOMM7 | translocase of outer mitochondrial membrane 7 |
TRAF6 | tumor-necrosis-factor-receptor-associated factor 6 |
TRX | reduced thioredoxin |
TRX-Px | thioredoxin peroxidase |
TSC1/2 | tuberous sclerosis protein 1 and 2 |
ULK | Unc-51-like kinase |
ULK1/2 | serine/threonine Unc-51 like kinase ½ |
UVRAG | UV radiation resistance-associated |
VDAC-1 | voltage-dependent anion channel-1 |
VPS34 | vacuolar protein sorting 34 |
WIPI2 | WD-repeat domain phosphoinositide-interacting 2 |
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Title | Type of Study | Autophagy Markers/Evaluation | Type of Cancer | ClinicalTrials.gov ID |
---|---|---|---|---|
Investigation of autophagy markers in endometrial polyps (Turkey) | Observational | Beclin 1 LC3A/B P62/ Immunohistochemistry ELISA | Endometrial polyp | NCT04706000 |
Association of autophagy-related genes, LncRNA and SNPs with colorectal cancer in egyptian population (Egypt) | Observational | In PBMC and tissue, the levels of expression of EIF4EBP1, HOTTIP and serum SNP HOTTIP rs1859168 | Colorectal cancer | NCT04729855 |
Identification of novel autophagy markers in bladder cancer patients (Egypt) | Observational | Atg7 (RTPCR) LC3A (immunohistochemistry) | Bladder cancer | NCT03254888 |
Immunohistochemical assessment of programmed death ligand 1 PDL-1 and autophagy marker LC3B in glioblastoma (Egypt) | Observational | LC3B (immunohistochemistry) | Glioblastoma | NCT04284306 |
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Zdanowicz, A.; Grosicka-Maciąg, E. The Interplay between Autophagy and Mitochondria in Cancer. Int. J. Mol. Sci. 2024, 25, 9143. https://doi.org/10.3390/ijms25179143
Zdanowicz A, Grosicka-Maciąg E. The Interplay between Autophagy and Mitochondria in Cancer. International Journal of Molecular Sciences. 2024; 25(17):9143. https://doi.org/10.3390/ijms25179143
Chicago/Turabian StyleZdanowicz, Aleksandra, and Emilia Grosicka-Maciąg. 2024. "The Interplay between Autophagy and Mitochondria in Cancer" International Journal of Molecular Sciences 25, no. 17: 9143. https://doi.org/10.3390/ijms25179143