Bortezomib modulated the autophagy-lysosomal pathway in a TFEB-dependent manner in multiple myeloma

Zhang, Rongjuan; Yang, Xinhong; Shi, Xiaomin; Xing, Enhong; Wang, Lihong; Hao, Changlai; Zhang, Zhihua

doi:10.1016/j.leukres.2024.107455

Cited by 1 publication

(1 citation statement)

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“…To monitor the autophagic activity, the lysosomal marker Lysotracker RED was used. Lysotracker has been used as an autophagy marker, even though it does not directly assess autophagic flux but rather stains and thus quantifies acidic proteins (58–60). The acidic protein content of a cell is correlated to the lysosomal load, and therefore, due to the organelles’ role in autophagy, Lysotracker can be used to study autophagic activity.…”

Section: Resultsmentioning

confidence: 99%

The ERK1/2-Elk1, JNK-cJun, and JAK-STAT Transcriptional Axes as Potential Bortezomib Resistance Mediators in Prostate Cancer

Kalampounias,

Zafeiropoulou,

Androutsopoulou

et al. 2024

Preprint

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The effectiveness of proteasome inhibitors against solid tumors is limited as the emergence of resistance is rapid. Although many mechanisms have been proposed and verified, no definite answer has been given, highlighting the complexity of the resistant phenotype. In this study, a Bortezomib-resistant prostate cancer cell line is created, and a broad-spectrum signaling pathway analysis is performed to identify differences and adaptations the resistant cells exhibit. Our findings highlight the upregulation and activation of Nf-κB, STAT3, cJun, and Elk1 transcription factors in the resistant cells and the subsequent evasion of apoptosis and induction of autophagy, which is constantly activated and substitutes the role of the ubiquitin-proteasome system (UPS). Additionally, assessment of the intracellular reactive oxygen species in resistant cells confirms their downregulation, which is theorized to be a consequence of metabolic changes, increased autophagic flux, and antioxidative enzyme action. The results of this study highlight the potential therapeutic targeting of key kinases and transcription factors, participating in the main signaling pathways and gene regulation of Bortezomib-resistant cells, that could re-sensitize the cells to proteasome inhibitors, thus surpassing the current limitations.

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Section: Resultsmentioning

confidence: 99%