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1.
J Biol Chem ; 300(9): 107670, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39128718

RESUMO

Mitochondrial Rho GTPases (MIRO1 and MIRO2) are primarily studied for their role as resident mitochondrial anchor proteins that facilitate mitochondria trafficking in neurons. However, it is now appreciated that these proteins have critical roles in cancer. In this review, we focus on examining the role of MIROs in cancer, including expression changes in tumors and the molecular mechanisms by which MIROs impact tumor cell growth, invasion, and metastasis. Additionally, we give an overview of how MIRO's functions in normal cells within the tumor microenvironment can support or inhibit tumor growth and metastasis. Although this is still an emerging field, the current consensus is that the MIROs primarily promote tumor progression of disparate tumor types. As mitochondrial proteins are now being targeted in the clinic, we discuss their potential as novel proteins to target in cancer.


Assuntos
Mitocôndrias , Neoplasias , Proteínas rho de Ligação ao GTP , Humanos , Proteínas rho de Ligação ao GTP/metabolismo , Proteínas rho de Ligação ao GTP/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Animais , Microambiente Tumoral , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética
2.
Proc Natl Acad Sci U S A ; 119(8)2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35177476

RESUMO

Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. In turn, this induces epithelial-mesenchymal transition (EMT), activates tumor cell movements through exaggerated mitochondrial dynamics, and promotes metastatic dissemination in vivo. In a small-molecule drug screen, compensatory activation of stress response (GCN2) and survival (Akt) signaling maintains the viability of Mic60-low tumors and provides a selective therapeutic vulnerability. These data demonstrate that acutely damaged, "ghost" mitochondria drive tumor progression and expose an actionable therapeutic target in metastasis-prone cancers.


Assuntos
Mitocôndrias/fisiologia , Metástase Neoplásica/fisiopatologia , Neoplasias/genética , Morte Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Transição Epitelial-Mesenquimal , Humanos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/fisiologia , Proteínas Mitocondriais/metabolismo , Proteínas Musculares/metabolismo , Invasividade Neoplásica/genética , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Processos Neoplásicos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais
3.
J Biol Chem ; 299(10): 105186, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37611829

RESUMO

Loss of protein kinase Cδ (PKCδ) activity renders cells resistant to DNA damaging agents, including irradiation; however, the mechanism(s) underlying resistance is poorly understood. Here, we have asked if metabolic reprogramming by PKCδ contributes to radioprotection. Analysis of global metabolomics showed that depletion of PKCδ affects metabolic pathways that control energy production and antioxidant, nucleotide, and amino acid biosynthesis. Increased NADPH and nucleotide production in PKCδ-depleted cells is associated with upregulation of the pentose phosphate pathway (PPP) as evidenced by increased activation of G6PD and an increase in the nucleotide precursor, 5-phosphoribosyl-1-pyrophosphate. Stable isotope tracing with U-[13C6] glucose showed reduced utilization of glucose for glycolysis in PKCδ-depleted cells and no increase in U-[13C6] glucose incorporation into purines or pyrimidines. In contrast, isotope tracing with [13C5, 15N2] glutamine showed increased utilization of glutamine for synthesis of nucleotides, glutathione, and tricarboxylic acid intermediates and increased incorporation of labeled glutamine into pyruvate and lactate. Using a glycolytic rate assay, we confirmed that anaerobic glycolysis is increased in PKCδ-depleted cells; this was accompanied by a reduction in oxidative phosphorylation, as assayed using a mitochondrial stress assay. Importantly, pretreatment of cells with specific inhibitors of the PPP or glutaminase prior to irradiation reversed radioprotection in PKCδ-depleted cells, indicating that these cells have acquired codependency on the PPP and glutamine for survival. Our studies demonstrate that metabolic reprogramming to increase utilization of glutamine and nucleotide synthesis contributes to radioprotection in the context of PKCδ inhibition.

4.
J Biol Chem ; 299(6): 104774, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37142218

RESUMO

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and ß1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions, or apoptosis. Expression of a Parkin Ub-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 Ub drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis, and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene, and its Ub by Parkin enables mitochondria-associated metastasis suppression.


Assuntos
Proteínas de Membrana , Ubiquitina-Proteína Ligases , Movimento Celular , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Humanos
5.
PLoS Biol ; 14(7): e1002507, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27389535

RESUMO

Mitochondria must buffer the risk of proteotoxic stress to preserve bioenergetics, but the role of these mechanisms in disease is poorly understood. Using a proteomics screen, we now show that the mitochondrial unfoldase-peptidase complex ClpXP associates with the oncoprotein survivin and the respiratory chain Complex II subunit succinate dehydrogenase B (SDHB) in mitochondria of tumor cells. Knockdown of ClpXP subunits ClpP or ClpX induces the accumulation of misfolded SDHB, impairing oxidative phosphorylation and ATP production while activating "stress" signals of 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and autophagy. Deregulated mitochondrial respiration induced by ClpXP targeting causes oxidative stress, which in turn reduces tumor cell proliferation, suppresses cell motility, and abolishes metastatic dissemination in vivo. ClpP is universally overexpressed in primary and metastatic human cancer, correlating with shortened patient survival. Therefore, tumors exploit ClpXP-directed proteostasis to maintain mitochondrial bioenergetics, buffer oxidative stress, and enable metastatic competence. This pathway may provide a "drugable" therapeutic target in cancer.


Assuntos
Endopeptidase Clp/metabolismo , Metabolismo Energético , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Neoplasias/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Endopeptidase Clp/genética , Feminino , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Proteômica/métodos , Interferência de RNA , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Survivina , Transplante Heterólogo
6.
Proc Natl Acad Sci U S A ; 112(28): 8638-43, 2015 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-26124089

RESUMO

Molecular therapies are hallmarks of "personalized" medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, "spatiotemporal" mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target.


Assuntos
Inibidores Enzimáticos/farmacologia , Mitocôndrias/efeitos dos fármacos , Invasividade Neoplásica , Inibidores de Fosfoinositídeo-3 Quinase , Transporte Biológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Citoesqueleto/metabolismo , Metabolismo Energético , Humanos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
7.
Pharmacol Res ; 102: 42-5, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26365877

RESUMO

Recent studies have demonstrated that tumor cells exposed to molecular therapy with PI3K antagonists redistribute their mitochondria to the peripheral cytoskeleton, fueling membrane dynamics, turnover of focal adhesion complexes and increased tumor cell motility and invasion. Although this process paradoxically increases metastatic propensity during molecular therapy, it also emphasizes a critical role of regional mitochondrial bioenergetics in tumor metabolic reprogramming and may offer prime therapeutic opportunities to prevent disseminated disease.


Assuntos
Antineoplásicos/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Adesões Focais/efeitos dos fármacos , Adesões Focais/metabolismo , Adesões Focais/patologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/metabolismo
8.
J Biol Chem ; 286(13): 11254-64, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21252239

RESUMO

Protein kinase C (PKC) isozymes are key signal transducers involved in normal physiology and disease and have been widely implicated in cancer progression. Despite our extensive knowledge of the signaling pathways regulated by PKC isozymes and their effectors, there is essentially no information on how individual members of the PKC family regulate gene transcription. Here, we report the first PKC isozyme-specific analysis of global gene expression by microarray using RNAi depletion of diacylglycerol/phorbol ester-regulated PKCs. A thorough analysis of this microarray data revealed unique patterns of gene expression controlled by PKCα, PKCδ, and PKCε, which are remarkably different in cells growing in serum or in response to phorbol ester stimulation. PKCδ is the most relevant isoform in controlling the induction of genes by phorbol ester stimulation, whereas PKCε predominantly regulates gene expression in serum. We also established that two PKCδ-regulated genes, FOSL1 and BCL2A1, mediate the apoptotic effect of phorbol esters or the chemotherapeutic agent etoposide in prostate cancer cells. Our studies offer a unique opportunity for establishing novel transcriptional effectors for PKC isozymes and may have significant functional and therapeutic implications.


Assuntos
Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Proteína Quinase C/metabolismo , Transcrição Gênica/fisiologia , Antineoplásicos Fitogênicos/farmacologia , Carcinógenos/farmacologia , Linhagem Celular , Etoposídeo/farmacologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Ésteres de Forbol/farmacologia , Proteína Quinase C/genética , Transcrição Gênica/efeitos dos fármacos
9.
Front Cell Dev Biol ; 10: 849962, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35356277

RESUMO

Mitochondria are highly dynamic organelles which can change their shape, via processes termed fission and fusion, in order to adapt to different environmental and developmental contexts. Due to the importance of these processes in maintaining a physiologically healthy pool of mitochondria, aberrant cycles of fission/fusion are often seen in pathological contexts. In this review we will discuss how dysregulated fission and fusion promote tumor progression. We focus on the molecular mechanisms involved in fission and fusion, discussing how altered mitochondrial fission and fusion change tumor cell growth, metabolism, motility, and invasion and, finally how changes to these tumor-cell intrinsic phenotypes directly and indirectly impact tumor progression to metastasis. Although this is an emerging field of investigation, the current consensus is that mitochondrial fission positively influences metastatic potential in a broad variety of tumor types. As mitochondria are now being investigated as vulnerable targets in a variety of cancer types, we underscore the importance of their dynamic nature in potentiating tumor progression.

10.
Mol Cancer Res ; 20(4): 607-621, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34992146

RESUMO

There is a continued need to identify novel therapeutic targets to prevent the mortality associated with prostate cancer. In this context, mitochondrial Rho GTPase 2 (MIRO2) mRNA was upregulated in metastatic prostate cancer compared with localized tumors, and higher MIRO2 levels were correlated with poor patient survival. Using human cell lines that represent androgen-independent or -sensitive prostate cancer, we showed that MIRO2 depletion impaired cell growth, colony formation, and tumor growth in mice. Network analysis of MIRO2's binding partners identified metabolism and cellular responses to extracellular stimuli as top overrepresented pathways. The top hit on our screen, General Control Nonderepressible 1 (GCN1), was overexpressed in prostate cancer, and interacted with MIRO2 in prostate cancer cell lines and in primary prostate cancer cells. Functional analysis of MIRO2 mutations present in patients with prostate cancer led to the identification of MIRO2 159L, which increased GCN1 binding. Importantly, MIRO2 was necessary for efficient GCN1-mediated GCN2 kinase signaling and induction of the transcription factor activating transcription factor 4 (ATF4) levels. Further, MIRO2's effect on regulating prostate cancer cell growth was mediated by ATF4. Finally, levels of activated GCN2 and ATF4 were correlated with MIRO2 expression in prostate cancer xenografts. Both MIRO2 and activated GCN2 levels were higher in hypoxic areas of prostate cancer xenografts. Overall, we propose that targeting the MIRO2-GCN1 axis may be a valuable strategy to halt prostate cancer growth. IMPLICATIONS: MIRO2/GCN1/GCN2 constitute a novel mitochondrial signaling pathway that controls androgen-independent and androgen-sensitive prostate cancer cell growth.


Assuntos
Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Fatores de Alongamento de Peptídeos/genética , Fatores de Alongamento de Peptídeos/metabolismo , Neoplasias da Próstata/genética , Proteínas Serina-Treonina Quinases , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Transativadores/metabolismo
11.
Cancers (Basel) ; 14(14)2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35884604

RESUMO

Triple-negative breast cancer (TNBC) often undergoes at least partial epithelial-to-mesenchymal transition (EMT) to facilitate metastasis. Identifying EMT-associated characteristics can reveal novel dependencies that may serve as therapeutic vulnerabilities in this aggressive breast cancer subtype. We found that NPC1, which encodes the lysosomal cholesterol transporter Niemann-Pick type C1 is highly expressed in TNBC as compared to estrogen receptor-positive (ER+) breast cancer, and is significantly elevated in high-grade disease. We demonstrated that NPC1 is directly targeted by microRNA-200c (miR-200c), a potent suppressor of EMT, providing a mechanism for its differential expression in breast cancer subtypes. The silencing of NPC1 in TNBC causes an accumulation of cholesterol-filled lysosomes, and drives decreased growth in soft agar and invasive capacity. Conversely, overexpression of NPC1 in an ER+ cell line increases invasion and growth in soft agar. We further identified TNBC cell lines as cholesterol auxotrophs, however, they do not solely depend on NPC1 for adequate cholesterol supply. The silencing of NPC1 in TNBC cell lines led to altered mitochondrial function and morphology, suppression of mTOR signaling, and accumulation of autophagosomes. A small molecule inhibitor of NPC1, U18666A, decreased TNBC proliferation and synergized with the chemotherapeutic drug, paclitaxel. This work suggests that NPC1 promotes aggressive characteristics in TNBC, and identifies NPC1 as a potential therapeutic target.

12.
J Biol Chem ; 285(34): 26033-40, 2010 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-20566643

RESUMO

Protein kinase Cepsilon (PKCepsilon), a diacyglycerol- and phorbol ester-responsive serine-threonine kinase, has been implicated in mitogenic and survival control, and it is markedly overexpressed in human tumors, including in prostate cancer. Although prostate cancer cells undergo apoptosis in response to phorbol ester stimulation via PKCdelta-mediated release of death factors, the involvement of PKCepsilon in this response is not known. PKCepsilon depletion by RNAi or expression of a dominant negative kinase-dead PKCepsilon mutant potentiated the apoptotic response of PMA and sensitized LNCaP cells to the death receptor ligand TNFalpha. On the other hand, overexpression of PKCepsilon by adenoviral means protected LNCaP cells against apoptotic stimuli. Interestingly, PKCepsilon RNAi depletion significantly enhanced the release of TNFalpha in response to PMA and greatly potentiated JNK activation by this cytokine. Further mechanistic analysis revealed that PMA fails to promote phosphorylation of Bad in Ser(112) in PKCepsilon-depleted LNCaP cells, whereas PKCepsilon overexpression greatly enhanced Bad phosphorylation. This effect was independent of Akt, ERK, or p90Rsk, well established kinases for Ser(112) in Bad. Moreover, expression of a S112A-Bad mutant potentiated PMA-induced apoptosis. Finally, we found that upon activation PKCepsilon accumulated in mitochondrial fractions in LNCaP cells and that Bad was a substrate of PKCepsilon in vitro. Our results established that PKCepsilon modulates survival in prostate cancer cells via multiple pathways.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteína Quinase C-épsilon/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Masculino , Fosforilação , Transdução de Sinais , Acetato de Tetradecanoilforbol/farmacologia , Proteína de Morte Celular Associada a bcl
13.
J Biol Chem ; 285(22): 16931-41, 2010 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-20335173

RESUMO

Although the family of chimaerin Rac-GAPs has recently gained significant attention for their involvement in development, cancer, and neuritogenesis, little is known about their molecular regulation. Chimaerins are activated by the lipid second messenger diacylglycerol via their C1 domain upon activation of tyrosine kinase receptors, thereby restricting the magnitude of Rac signaling in a receptor-regulated manner. Here we identified a novel regulatory mechanism for beta2-chimaerin via phosphorylation. Epidermal growth factor or the phorbol ester phorbol 12-myristate 13-acetate caused rapid phosphorylation of beta2-chimaerin on Ser(169) located in the SH2-C1 domain linker region via protein kinase Cdelta, which retained beta2-chimaerin in the cytosol and prevented its C1 domain-mediated translocation to membranes. Furthermore, despite the fact that Ser(169) phosphorylation did not alter intrinsic Rac-GAP activity in vitro, a non-phosphorylatable beta2-chimaerin mutant was highly sensitive to translocation, and displayed enhanced association with activated Rac, enhanced Rac-GAP activity, and anti-migratory properties when expressed in cells. Our results not only revealed a novel regulatory mechanism that facilitates Rac activation, but also identified a novel mechanism of cross-talk between diacylglycerol receptors that restricts beta2-chimaerin relocalization and activation.


Assuntos
Diglicerídeos/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Proteínas de Neoplasias/química , Proteína Quinase C-delta/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Células COS , Chlorocebus aethiops , Citosol/metabolismo , Diglicerídeos/química , Células HeLa , Humanos , Camundongos , Mutação , Neurônios/metabolismo , Ésteres de Forbol/química , Fosforilação , Proteína Quinase C/metabolismo , Proteínas Tirosina Quinases/química , Transdução de Sinais
14.
Dev Cell ; 56(14): 2029-2042.e5, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34171288

RESUMO

Mitochondria are critical metabolic and signaling hubs, and dysregulated mitochondrial homeostasis is implicated in many diseases. Degradation of damaged mitochondria by selective GABARAP/LC3-dependent macro-autophagy (mitophagy) is critical for maintaining mitochondrial homeostasis. To identify alternate forms of mitochondrial quality control that functionally compensate if mitophagy is inactive, we selected for autophagy-dependent cancer cells that survived loss of LC3-dependent autophagosome formation caused by inactivation of ATG7 or RB1CC1/FIP200. We discovered rare surviving autophagy-deficient clones that adapted to maintain mitochondrial homeostasis after gene inactivation and identified two enhanced mechanisms affecting mitochondria including mitochondrial dynamics and mitochondrial-derived vesicles (MDVs). To further understand these mechanisms, we quantified MDVs via flow cytometry and confirmed an SNX9-mediated mechanism necessary for flux of MDVs to lysosomes. We show that the autophagy-dependent cells acquire unique dependencies on these processes, indicating that these alternate forms of mitochondrial homeostasis compensate for loss of autophagy to maintain mitochondrial health.


Assuntos
Autofagia , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/patologia , Dinâmica Mitocondrial , Mitofagia , Nexinas de Classificação/metabolismo , Vesículas Transportadoras/fisiologia , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Endossomos/metabolismo , Humanos , Lisossomos , Proteínas Associadas aos Microtúbulos/genética , Mitocôndrias/metabolismo , Nexinas de Classificação/genética
15.
Cancer Rep (Hoboken) ; 3(1): e1157, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32671955

RESUMO

BACKGROUND: Mammalian cells must constantly reprogram the distribution of mitochondria in order to meet the local demands for energy, calcium, redox balance, and other mitochondrial functions. Mitochondrial localization inside the cell is a result of a combination of movement along the microtubule tracks plus anchoring to actin filaments. RECENT FINDINGS: Recent advances show that subcellular distribution of mitochondria can regulate tumor cell growth, proliferation/motility plasticity, metastatic competence, and therapy responses in tumors. In this review, we discuss our current understanding of the mechanisms by which mitochondrial subcellular distribution is regulated in tumor cells. CONCLUSIONS: Mitochondrial trafficking is dysregulated in tumors. Accumulation of mitochondria at the leading edge of the cell supports energy expensive processes of focal adhesion dynamics, cell membrane dynamics, migration, and invasion.


Assuntos
Mitocôndrias/fisiologia , Metástase Neoplásica , Trifosfato de Adenosina/metabolismo , Animais , Movimento Celular , Adesões Focais , Humanos , Proteínas de Membrana/fisiologia , Microtúbulos/fisiologia , Cadeias Pesadas de Miosina/fisiologia , Miosina Tipo V/fisiologia , Miosinas/fisiologia , Invasividade Neoplásica , Proteínas do Tecido Nervoso/fisiologia , Transdução de Sinais
16.
Cancer Lett ; 471: 72-87, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31838085

RESUMO

Androgen receptor (AR) signaling plays a central role in metabolic reprogramming for prostate cancer (PCa) growth and progression. Mitochondria are metabolic powerhouses of the cell and support several hallmarks of cancer. However, the molecular links between AR signaling and the mitochondria that support the metabolic demands of PCa cells are poorly understood. Here, we demonstrate increased levels of dynamin-related protein 1 (DRP1), a mitochondrial fission mediator, in androgen-sensitive and castration-resistant AR-driven PCa. AR signaling upregulates DRP1 to form the VDAC-MPC2 complex, increases pyruvate transport into mitochondria, and supports mitochondrial metabolism, including oxidative phosphorylation and lipogenesis. DRP1 inhibition activates the cellular metabolic stress response, which involves AMPK phosphorylation, induction of autophagy, and the ER unfolded protein response, and attenuates androgen-induced proliferation. Additionally, DRP1 expression facilitates PCa cell survival under diverse metabolic stress conditions, including hypoxia and oxidative stress. Moreover, we found that increased DRP1 expression was indicative of poor prognosis in patients with castration-resistant PCa. Collectively, our findings link androgen signaling-mediated mitochondrial dynamics to metabolic reprogramming; moreover, they have important implications for understanding PCa progression.


Assuntos
Androgênios/metabolismo , Dinaminas/biossíntese , Mitocôndrias/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Ciclo do Ácido Cítrico , Di-Hidrotestosterona/farmacologia , Dinaminas/antagonistas & inibidores , Dinaminas/genética , Dinaminas/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Masculino , Dinâmica Mitocondrial , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Fosforilação Oxidativa , Células PC-3 , Neoplasias de Próstata Resistentes à Castração/patologia , Piruvatos/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Regulação para Cima , Canais de Ânion Dependentes de Voltagem/metabolismo
17.
Sci Signal ; 13(642)2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32723812

RESUMO

Mitochondria are signaling hubs in eukaryotic cells. Here, we showed that the mitochondrial FUN14 domain-containing protein-1 (FUNDC1), an effector of Parkin-independent mitophagy, also participates in cellular plasticity by sustaining oxidative bioenergetics, buffering ROS production, and supporting cell proliferation. Targeting this pathway in cancer cells suppressed tumor growth but rendered transformed cells more motile and invasive in a manner dependent on ROS-mediated mitochondrial dynamics and mitochondrial repositioning to the cortical cytoskeleton. Global metabolomics and proteomics profiling identified a FUNDC1 interactome at the mitochondrial inner membrane, comprising the AAA+ protease, LonP1, and subunits of oxidative phosphorylation, complex V (ATP synthase). Independently of its previously identified role in mitophagy, FUNDC1 enabled LonP1 proteostasis, which in turn preserved complex V function and decreased ROS generation. Therefore, mitochondrial reprogramming by a FUNDC1-LonP1 axis controls tumor cell plasticity by switching between proliferative and invasive states in cancer.


Assuntos
Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Células A549 , Animais , Humanos , Células MCF-7 , Proteínas de Membrana/genética , Camundongos , Proteínas Mitocondriais/genética , Células NIH 3T3 , Proteínas de Neoplasias/genética , Neoplasias/genética , Células PC-3
18.
Cancer Discov ; 10(9): 1282-1295, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32499221

RESUMO

Older patients with melanoma (>50 years old) have poorer prognoses and response rates to targeted therapy compared with young patients (<50 years old), which can be driven, in part, by the aged microenvironment. Here, we show that aged dermal fibroblasts increase the secretion of neutral lipids, especially ceramides. When melanoma cells are exposed to the aged fibroblast lipid secretome, or cocultured with aged fibroblasts, they increase the uptake of lipids via the fatty acid transporter FATP2, which is upregulated in melanoma cells in the aged microenvironment and known to play roles in lipid synthesis and accumulation. We show that blocking FATP2 in melanoma cells in an aged microenvironment inhibits their accumulation of lipids and disrupts their mitochondrial metabolism. Inhibiting FATP2 overcomes age-related resistance to BRAF/MEK inhibition in animal models, ablates tumor relapse, and significantly extends survival time in older animals. SIGNIFICANCE: These data show that melanoma cells take up lipids from aged fibroblasts, via FATP2, and use them to resist targeted therapy. The response to targeted therapy is altered in aged individuals because of the influences of the aged microenvironment, and these data suggest FATP2 as a target to overcome resistance.See related commentary by Montal and White, p. 1255.This article is highlighted in the In This Issue feature, p. 1241.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Coenzima A Ligases/metabolismo , Fibroblastos/metabolismo , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Senescência Celular , Técnicas de Cocultura , Coenzima A Ligases/antagonistas & inibidores , Derme/citologia , Derme/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Queratinócitos/metabolismo , Metabolismo dos Lipídeos , Melanoma/patologia , Terapia de Alvo Molecular/métodos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/patologia , Microambiente Tumoral
19.
Apoptosis ; 14(4): 392-408, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19169823

RESUMO

Cellular senescence is a potent anti-cancer mechanism controlled by tumor suppressor genes, particularly p53 and pRb, which is characterized by the irreversible loss of proliferation. Senescence induced by DNA damage, oncogenic stimulation, or excessive mitogenic input, serves as a barrier that counteracts cancer progression. Emerging evidence in cellular and in in vivo models revealed the involvement of additional signaling players in senescence, including PML, CK2, Bcl-2, PI3K effectors such as Rheb, Rho small GTPases, and cytokines. Recent studies have also implicated protein kinase C (PKC) isozymes as modulators of senescence phenotypes and showed that phorbol esters, widely used PKC activators, can induce senescence in a number of cancer cells. These novel findings suggest a complex array of cross-talks between senescence pathways and may have significant implications in cancer therapy.


Assuntos
Envelhecimento/genética , Transformação Celular Neoplásica/genética , Senescência Celular/fisiologia , Neoplasias/genética , Transdução de Sinais/genética , Apoptose , Modelos Biológicos
20.
Methods Enzymol ; 446: 123-39, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18603119

RESUMO

Protein kinase C (PKC) isozymes catalyze the phosphorylation of substrates that play key roles in the control in proliferation, differentiation, and survival. Treatment of cells with phorbol esters, activators of classical and novel PKC isozymes, leads to a plethora of responses in a strict cell-type-dependent specific manner. Interestingly, a few cell models undergo apoptosis in response to phorbol ester stimulation, including androgen-dependent prostate cancer cells. This effect involves the autocrine secretion of death factors and activation of the extrinsic apoptotic cascade. We have recently found that in other models, such as lung cancer cells, phorbol esters lead to irreversible growth arrest and senescence. This chapter describes the methods we use to assess these phorbol ester responses in cancer cell models, focusing on apoptosis and senescence.


Assuntos
Apoptose/fisiologia , Proteína Quinase C-delta/fisiologia , Acetato de Tetradecanoilforbol/farmacologia , Adenoviridae/enzimologia , Apoptose/efeitos dos fármacos , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Humanos , Masculino , Neoplasias da Próstata , Proteína Quinase C-alfa/fisiologia , Proteína Quinase C-épsilon/fisiologia , Interferência de RNA
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