Abstract:Autophagy is a highly complicated process with participation of large numbers of autophagy-related proteins. Under nutrient starvation, autophagy promotes cell survival by breaking down nonessential cellular components for recycling use. However, due to its high complexity, molecular mechanism of autophagy is still not fully understood. In the present study, we report a novel autophagy-related protein TM9SF4, which plays a functional role in the induction phase of autophagic process. TM9SF4 proteins were abund… Show more
“…1i ). Taken together, these data showed that PPI induced autophagosome formation via TM9SF4-mTOR pathway, consistent with recent studies 30 , 32 . Fig.…”
Section: Resultssupporting
confidence: 93%
“…Cancer cells under microenvironmental stress (including low pH) use to cannibalize other cells 29 . TM9SF4 has been recently reported as an important regulator of autophagy 30 , 31 and cannibalism 29 . Suppression of TM9SF4 by siRNAs attenuated the PPI-stimulated dephosphorylation of mTOR, RPS6, and 4E-BP1 (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…These results showed that the impacts of PPI on autophagy were not merely the autophagic flux blockage in low pH condition 19 . Recent studies also found that TM9SF4 could regulate autophagy initiation in response to nutrient starvation by inhibiting the nutrient-sensing kinase complex mTORC1 30 . Indeed, we found that PPI markedly reduced the mTOR activity consistent with previous reports 25 , as indicated by dephosphorylation of mTOR, 4E-BP1 and RPS6.…”
Proton pump inhibitors (PPIs) play a role in antitumor activity, with studies showing specialized impacts of PPIs on cancer cell apoptosis, metastasis, and autophagy. In this study, we demonstrated that pantoprazole (PPI) increased autophagosomes formation and affected autophagic flux depending on the pH conditions. PPI specifically elevated SQSTM1 protein levels by increasing SQSTM1 transcription via NFE2L2 activation independent of the specific effect of PPI on autophagic flux. Via decreasing proteasome subunits expression, PPI significantly impaired the function of the proteasome, accompanied by the accumulation of undegraded poly-ubiquitinated proteins. Notably, PPI-induced autophagy functioned as a downstream response of proteasome inhibition by PPI, while suppressing protein synthesis abrogated autophagy. Blocking autophagic flux in neutral pH condition or further impairing proteasome function with proteasome inhibitors, significantly aggravated PPI cytotoxicity by worsening protein degradation ability. Interestingly, under conditions of mitochondrial stress, PPI showed significant synergism when combined with Bcl-2 inhibitors. Taken together, these findings provide a new understanding of the impact of PPIs on cancer cells’ biological processes and highlight the potential to develop more efficient and effective combination therapies.
“…1i ). Taken together, these data showed that PPI induced autophagosome formation via TM9SF4-mTOR pathway, consistent with recent studies 30 , 32 . Fig.…”
Section: Resultssupporting
confidence: 93%
“…Cancer cells under microenvironmental stress (including low pH) use to cannibalize other cells 29 . TM9SF4 has been recently reported as an important regulator of autophagy 30 , 31 and cannibalism 29 . Suppression of TM9SF4 by siRNAs attenuated the PPI-stimulated dephosphorylation of mTOR, RPS6, and 4E-BP1 (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…These results showed that the impacts of PPI on autophagy were not merely the autophagic flux blockage in low pH condition 19 . Recent studies also found that TM9SF4 could regulate autophagy initiation in response to nutrient starvation by inhibiting the nutrient-sensing kinase complex mTORC1 30 . Indeed, we found that PPI markedly reduced the mTOR activity consistent with previous reports 25 , as indicated by dephosphorylation of mTOR, 4E-BP1 and RPS6.…”
Proton pump inhibitors (PPIs) play a role in antitumor activity, with studies showing specialized impacts of PPIs on cancer cell apoptosis, metastasis, and autophagy. In this study, we demonstrated that pantoprazole (PPI) increased autophagosomes formation and affected autophagic flux depending on the pH conditions. PPI specifically elevated SQSTM1 protein levels by increasing SQSTM1 transcription via NFE2L2 activation independent of the specific effect of PPI on autophagic flux. Via decreasing proteasome subunits expression, PPI significantly impaired the function of the proteasome, accompanied by the accumulation of undegraded poly-ubiquitinated proteins. Notably, PPI-induced autophagy functioned as a downstream response of proteasome inhibition by PPI, while suppressing protein synthesis abrogated autophagy. Blocking autophagic flux in neutral pH condition or further impairing proteasome function with proteasome inhibitors, significantly aggravated PPI cytotoxicity by worsening protein degradation ability. Interestingly, under conditions of mitochondrial stress, PPI showed significant synergism when combined with Bcl-2 inhibitors. Taken together, these findings provide a new understanding of the impact of PPIs on cancer cells’ biological processes and highlight the potential to develop more efficient and effective combination therapies.
“…TUNEL assay. TUNEL staining in tissue sections was conducted using the In Situ Cell Death Detection Kit (Roche, Switzerland) as described elsewhere 25 . Briefly, mASMCs were fixed with 4% paraformaldehyde (PFA) and permeabilized with 0.1% Triton X-100 in 0.1% sodium citrate.…”
Transient receptor potential channel M2 (TRPM2) is a Ca2+-permeable channel that is activated by reactive oxygen species (ROS). In many cell types, ROS activate TRPM2 to induce excessive Ca2+ influx, resulting in Ca2+ overload and consequent cell death. Recent studies suggest that TRPM2 may also regulate autophagy in pericytes and cancer cells by acting on the early step of autophagy, i.e. autophagic induction. However, there is no report on the role of TRPM2 in autophagic degradation, which is the late stage of autophagy. In the present study, we found abundant TRPM2 expression in lysosomes/autolysosomes in the primary cultured mouse aortic smooth muscle cells (mASMCs). Nutrient starvation stimulated autophagic flux in mASMCs mainly by promoting autophagic degradation. This starvation-induced autophagic degradation was reduced by TRPM2 knockout. Importantly, starvation-induced lysosomal/autolysosomal acidification and cell death were also substantially reduced by TRPM2 knockout. Taken together, the present study uncovered a novel mechanism that lysosomal TRPM2 facilitates lysosomal acidification to stimulate excessive autolysosome degradation and consequent cell death.
“…TM9SF4 knockdown inhibits the cannibalism phenomenon (Lozupone et al, 2009). TM9SF4 can also regulate autophagy; it localizes to lysosomes and has been shown to regulate autophagy initiation in response to nutrient starvation by inhibiting the nutrient-sensing kinase complex mammalian target of rapamycin complex 1 (mTORC1), and it knockdown inhibits the autophagy (Sun et al, 2018). TM9SF4 is thought to suppress both cannibalism and autophagy, indicating a relationship between autophagy and cannibalism.…”
Section: Molecular Mechanism Of Cannibalismmentioning
The term cell-in-cell, morphologically, refers to the presence of one cell within another. This phenomenon can occur in tumors but also among non-tumor cells. The cell-in-cell phenomenon was first observed 100 years ago, and it has since been found in a variety of tumor types. Recently, increasing attention has been paid to this phenomenon and the underlying mechanism has gradually been elucidated. There are three main related process: cannibalism, emperipolesis, and entosis. These processes are affected by many factors, including the tumor microenvironment, mitosis, and genetic factors. There is considerable evidence to suggest that the cell-in-cell phenomenon is associated with the prognosis of cancers, and it promotes tumor progression in most situations. Notably, in pancreatic cancer, the cell-in-cell phenomenon is associated with reduced metastasis, which is the opposite of what happens in other tumor types. Thus, it can also inhibit tumor progression. Studies show that cell-in-cell structure formation is affected by the tumor microenvironment, and that it may lead to changes in cellular characteristics. In this review, we summarize the different cell-in-cell processes and discuss their role in tumor progression and how they are regulated by different mechanisms.
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