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O papel de TRIB2 na autofagia
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Advisor(s)
Abstract(s)
O cancro é uma das principais causas de morte no mundo. As células cancerígenas beneficiam
de processos celulares como a autofagia para sobreviver a condições de stress no seu
microambiente, como privação de nutrientes, baixos níveis de energia e hipóxia. Em vários
tipos de tumor a via de PI3K/AKT está hiperactiva, o que permite que a cinase mTOR, regulador
da proliferação celular, apoptose e regulador negativo da autofagia, esteja ativo. Na quimioterapia
convencional são utilizados inibidores de mTOR e PI3K/AKT, que consequentemente
ativam a autofagia, o que resulta na sobrevivência das células cancerígenas e resistência aos
tratamentos. A proteína TRIB2 é uma pseudocinase descrita como um oncogene que favorece
a ativação da via de PI3K/AKT. É um membro da família TRIBBLES que inclui TRIB1 e
TRIB3. Previamente foi publicado por diferentes grupos de investigação que a sobreexpressão
de TRIB3 parece ter em vários contextos tumorais uma ação oposta à exercida por TRIB2,
conferindo características de gene supressor de tumor. No contexto autofágico, TRIB3 parece
suprimir a indução da autofagia conferindo às células acumulação de fatores promotores de
tumor. Tendo em conta estes dados, propusemos estudar o papel de TRIB2 no processo autofágico.
Sabendo que TRIB2 e TRIB3 parecem exercer em determinadas circunstâncias papéis
antagónicos, a nossa hipótese é que tumores com elevados níveis de TRIB2 levariam a um
aumento no fluxo autofágico.
Os nossos dados demonstraram que células com sobreexpressão de TRIB2 apresentam
níveis reduzidos de expressão de genes autofágicos. A análise de autofagossomas e autolisossomas
por microscopia confocal permitiu concluir que a dinâmica do fluxo autofágico é menor
em células que sobreexpressam TRIB2. Quando analisámos o impacto da presença de TRIB2,
quando a autofagia está bloqueada, verificaram-se níveis elevados de morte celular, o que indica
que células com TRIB2 são mais vulneráveis ao bloqueio da autofagia. Assim, concluímos
que a nossa hipótese é refutada e que TRIB2 inibe o fluxo autofágico. O nosso estudo contribui
para o conhecimento de TRIB2 na autofagia, e vem reforçar a importância deste biomarcador
tumoral na terapêutica de tumores com elevados níveis de TRIB2. No entanto é necessário
explorar o mecanismo pelo qual a proteína TRIB2 inibe a autofagia. Em suma, pacientes com
elevados níveis de TRIB2 podem beneficiar de compostos que inibam diretamente a via de
PI3K/AKT e o fluxo autofágico.
Cancer is one of the main causes of death in the world. Cancer cells benefit from cellular processes such as autophagy to survive stressful conditions in their microenvironment, such as nutrient deprivation, low energy levels, and hypoxia. In several tumor types, the PI3K/AKT pathway is hyperactivated, which allows the mTOR kinase, a major regulator of cell proliferation, apoptosis, and negative regulator of autophagy, to be active. In conventional chemotherapy, mTOR and PI3K/AKT inhibitors are used, which consequently activate autophagy, resulting in cancer cell survival and resistance to treatments. The TRIB2 protein is a pseudokinase described as an oncogene that contributes to PI3K/AKT pathway activation. It is a member of the TRIBBLES family, which also includes TRIB1 and TRIB3. Previously, different research groups reported that TRIB3 overexpression appears to have the opposite effect of TRIB2 in several tumor contexts, conferring tumor suppressor gene characteristics. TRIB3 appears to suppress autophagy induction in the autophagic context by allowing cells to accumulate tumorpromoting factors. Taking these data together, we proposed to study the role of TRIB2 in the autophagic process. It has been proposed that TRIB2 and TRIB3 may have antagonistic roles under certain circunstances, our hypothesis is that tumors with high levels of TRIB2 would lead to an increase in autophagic flux. Our data demonstrated that cells overexpressing TRIB2 have reduced levels of autophagic gene expression. Analysis of autophagosomes and autolysosomes by confocal microscopy allowed us to conclude that autophagic flux dynamics are lower in cells overexpressing TRIB2. When we analyzed the impact of TRIB2 presence when autophagy is blocked, high levels of cell death were observed, indicating that cells with more TRIB2 are more vulnerable to autophagy blockage. However, we conclude that our hypothesis is refuted and that TRIB2 inhibits autophagic flux. Our study contributes to the knowledge of TRIB2 in autophagy and reinforces the importance of this tumor biomarker in the therapy of tumors with high levels of TRIB2. However, it is necessary to explore the mechanism by which the TRIB2 protein inhibits autophagy. In summary, patients with high levels of TRIB2 may benefit from compounds that directly inhibit the PI3K/AKT pathway and autophagic flux.
Cancer is one of the main causes of death in the world. Cancer cells benefit from cellular processes such as autophagy to survive stressful conditions in their microenvironment, such as nutrient deprivation, low energy levels, and hypoxia. In several tumor types, the PI3K/AKT pathway is hyperactivated, which allows the mTOR kinase, a major regulator of cell proliferation, apoptosis, and negative regulator of autophagy, to be active. In conventional chemotherapy, mTOR and PI3K/AKT inhibitors are used, which consequently activate autophagy, resulting in cancer cell survival and resistance to treatments. The TRIB2 protein is a pseudokinase described as an oncogene that contributes to PI3K/AKT pathway activation. It is a member of the TRIBBLES family, which also includes TRIB1 and TRIB3. Previously, different research groups reported that TRIB3 overexpression appears to have the opposite effect of TRIB2 in several tumor contexts, conferring tumor suppressor gene characteristics. TRIB3 appears to suppress autophagy induction in the autophagic context by allowing cells to accumulate tumorpromoting factors. Taking these data together, we proposed to study the role of TRIB2 in the autophagic process. It has been proposed that TRIB2 and TRIB3 may have antagonistic roles under certain circunstances, our hypothesis is that tumors with high levels of TRIB2 would lead to an increase in autophagic flux. Our data demonstrated that cells overexpressing TRIB2 have reduced levels of autophagic gene expression. Analysis of autophagosomes and autolysosomes by confocal microscopy allowed us to conclude that autophagic flux dynamics are lower in cells overexpressing TRIB2. When we analyzed the impact of TRIB2 presence when autophagy is blocked, high levels of cell death were observed, indicating that cells with more TRIB2 are more vulnerable to autophagy blockage. However, we conclude that our hypothesis is refuted and that TRIB2 inhibits autophagic flux. Our study contributes to the knowledge of TRIB2 in autophagy and reinforces the importance of this tumor biomarker in the therapy of tumors with high levels of TRIB2. However, it is necessary to explore the mechanism by which the TRIB2 protein inhibits autophagy. In summary, patients with high levels of TRIB2 may benefit from compounds that directly inhibit the PI3K/AKT pathway and autophagic flux.
Description
Keywords
TRIB2 Autofagia Marcadores autofágicos mTOR