TFEB Supports Pancreatic Cancer Growth through the Transcriptional Regulation of Glutaminase

Kim, Ji Hye; Lee, Jin Young; Cho, Young-Ra; Lee, So‐Yeon; Sung, Gi‐Jun; Shin, Dong Myung; Choi, Kyung‐Chul; Son, Jaekyoung

doi:10.3390/cancers13030483

Cited by 21 publications

(13 citation statements)

References 41 publications

(37 reference statements)

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“…We assessed whether MIA shTFEB cells could develop orthotopic tumors to further support the notion that TFEB plays a significant role in PDAC growth. The impact of TFEB knockdown and its family members TFE3 and MITF on PDAC tumor growth has been evaluated in subcutaneous xenografts [ 35 , 37 ], but not in orthotopic models, that better recapitulate human disease. We found that tumors were significantly smaller in MIA shTFEB , than MIA shNT cells, indicating that TFEB contributes to PDAC tumor growth (Fig.…”

Section: Resultsmentioning

confidence: 99%

Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms

et al. 2023

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Gemcitabine is a first-line treatment agent for pancreatic ductal adenocarcinoma (PDAC). Contributing to its cytotoxicity, this chemotherapeutic agent is primarily a DNA replication inhibitor that also induces DNA damage. However, its therapeutic effects are limited owing to chemoresistance. Evidence in the literature points to a role for autophagy in restricting the efficacy of gemcitabine. Autophagy is a catabolic process in which intracellular components are delivered to degradative organelles lysosomes. Interfering with this process sensitizes PDAC cells to gemcitabine. It is consequently inferred that autophagy and lysosomal function need to be tightly regulated to maintain homeostasis and provide resistance to environmental stress, such as those imposed by chemotherapeutic drugs. However, the mechanism(s) through which gemcitabine promotes autophagy remains elusive, and the impact of gemcitabine on lysosomal function remains largely unexplored. Therefore, we applied complementary approaches to define the mechanisms triggered by gemcitabine that support autophagy and lysosome function. We found that gemcitabine elicited ERK-dependent autophagy in PDAC cells, but did not stimulate ERK activity or autophagy in non-tumoral human pancreatic epithelial cells. Gemcitabine also promoted transcription factor EB (TFEB)-dependent lysosomal function in PDAC cells. Indeed, treating PDAC cells with gemcitabine caused expansion of the lysosomal network, as revealed by Lysosome associated membrane protein-1 (LAMP1) and LysoTracker staining. More specific approaches have shown that gemcitabine promotes the activity of cathepsin B (CTSB), a cysteine protease playing an active role in lysosomal degradation. We showed that lysosomal function induced by gemcitabine depends on TFEB, the master regulator of autophagy and lysosomal biogenesis. Interfering with TFEB function considerably limited the clonogenic growth of PDAC cells and hindered the capacity of TFEB-depleted PDAC cells to develop orthotopic tumors.

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Section: Resultsmentioning

confidence: 99%

Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms

et al. 2023

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“…In contrast, TFEB overexpression seems to promote the development of some tumors [ 140 , 141 , 142 ]. Considering this, it is possible that the therapeutic use of TFEB activation may be limited by its oncogenic potential.…”

Section: Lysosomal Opportunities For Intervention In Agingmentioning

confidence: 99%

Age-Related Lysosomal Dysfunctions

Guerrero‐Navarro

Jansen-Duerr

Cavinato

2022

Cells

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Organismal aging is normally accompanied by an increase in the number of senescent cells, growth-arrested metabolic active cells that affect normal tissue function. These cells present a series of characteristics that have been studied over the last few decades. The damage in cellular organelles disbalances the cellular homeostatic processes, altering the behavior of these cells. Lysosomal dysfunction is emerging as an important factor that could regulate the production of inflammatory molecules, metabolic cellular state, or mitochondrial function.

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“…While TFEB-driven autophagy and endolysosomal biogenesis delays aging via the clearance of toxic macromolecules, unremitting activation of TFEB can paradoxically shorten lifespan [ 141 ]. Either the overexpression and/or constitutive nuclear localization of TFEB and TFE3 promote the growth of various types of cancer [ 226 , 227 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 ]. Additionally, amplification of the MITF locus and functional upregulation of MITF are potent drivers of melanoma [ 213 , 241 , 242 , 243 , 244 , 245 , 246 ].…”

Section: Regulation Of Lifespan By Ion Channels Involved In Autophagy...mentioning

confidence: 99%

Regulation of Aging and Longevity by Ion Channels and Transporters

Venkatachalam

2022

Cells

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Despite significant advances in our understanding of the mechanisms that underlie age-related physiological decline, our ability to translate these insights into actionable strategies to extend human healthspan has been limited. One of the major reasons for the existence of this barrier is that with a few important exceptions, many of the proteins that mediate aging have proven to be undruggable. The argument put forth here is that the amenability of ion channels and transporters to pharmacological manipulation could be leveraged to develop novel therapeutic strategies to combat aging. This review delves into the established roles for ion channels and transporters in the regulation of aging and longevity via their influence on membrane excitability, Ca2+ homeostasis, mitochondrial and endolysosomal function, and the transduction of sensory stimuli. The goal is to provide the reader with an understanding of emergent themes, and prompt further investigation into how the activities of ion channels and transporters sculpt the trajectories of cellular and organismal aging.

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TFEB Supports Pancreatic Cancer Growth through the Transcriptional Regulation of Glutaminase

Cited by 21 publications

References 41 publications

Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms

Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms

Age-Related Lysosomal Dysfunctions

Regulation of Aging and Longevity by Ion Channels and Transporters

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