Carboxyl group-modified myoglobin shows membrane-permeabilizing activity

Shi, Yijun; Lee, Yuan–Chin; Wang, Liangjun; Chiou, Jing-Ting; Tseng, Bo-Yang; Chang, Long‐Sen

doi:10.1016/j.abb.2022.109371

Cited by 1 publication

(5 citation statements)

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“…Notably, carboxyl group-modified LA with a molten globule conformation exhibits cytotoxicity in U937 and breast cancer MCF-7 cells [11,12]. Together with the finding that modification of the carboxyl groups causes dramatic distortion of the Mb structure [25], our results underscore the idea that conformational changes are related to SEM-Mb cytotoxicity. Previous studies have indicated that the apo-Mb 56-131 peptide exhibits membrane-perturbing activity in physiological solutions, whereas apo-Mb and Mb failed to show this activity [17].…”

Section: Discussionsupporting

confidence: 66%

“…Notably, Mb does not show cytotoxic activity prior to modification of the carboxyl group. Together with the finding that carboxyl group modification leads to conformational distortion in Mb [25], the data from this study highlight that chemical modification is a viable strategy for exploring intrinsic activities hindered by the conformation of protein. Furthermore, our data suggest that the carboxyl group-modified Mb is a potential structural template for the generation of tumoricidal proteins.…”

Section: Discussionmentioning

confidence: 57%

“…Chemical modification of the carboxyl groups in Mb with semicarbazide (Supplementary Figure S3) was conducted according to the procedure described in [25]. A MALDI-TOF analysis showed that there were approximately 19 semicarbazide-conjugated carboxyl groups in the SEM-Mb.…”

Section: Modification Of Mb With Semicarbazidementioning

confidence: 99%

“…A MALDI-TOF analysis showed that there were approximately 19 semicarbazide-conjugated carboxyl groups in the SEM-Mb. Measurement of circular dichroism spectra indicated that the carboxyl group modification profoundly distorted the secondary structure of Mb [25].…”

Section: Modification Of Mb With Semicarbazidementioning

confidence: 99%

“…As modification of the carboxyl group in LA with semicarbazide simultaneously changed its conformation and conferred the protein with anti-cancer effects [8], we envisioned the possibility of distorting the α-helical structure of Mb through carboxyl group modification to generate anti-cancer activity. Recent studies have shown that modification of the carboxyl group in Mb with semicarbazide profoundly distorts its gross structure [25]. Therefore, in this study, we investigated the cytotoxicity of semicarbazide-modified Mb (SEM-Mb).…”

Section: Introductionmentioning

confidence: 99%

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Carboxyl Group-Modified Myoglobin Induces TNF-α-Mediated Apoptosis in Leukemia Cells

et al. 2022

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Previous studies have shown that chemical modification may increase the activity of proteins or confer novel activity to proteins. Some studies have indicated that myoglobin (Mb) is cytotoxic; however, the underlying mechanisms remain unclear. In this study, we investigated whether chemical modification of the carboxyl group by semicarbazide could promote the Mb cytotoxicity in human leukemia U937 cells and the underlying mechanism of semicarbazide-modified myoglobin (SEM-Mb)-induced U937 cell death. The semicarbazide-modified Mb (SEM-Mb) induced U937 cell apoptosis via the production of cleaved caspase-8 and t-Bid, while silencing of FADD abolished this effect. These findings suggest that SEM-Mb can induce U937 cell death by activating the death receptor-mediated pathway. The SEM-Mb inhibited miR-99a expression, leading to increased NOX4 mRNA and protein expression, which promoted SIRT3 degradation, and, in turn, induced ROS-mediated p38 MAPK phosphorylation. Activated p38 MAPK stimulated miR-29a-dependent tristetraprolin (TTP) mRNA decay. Downregulation of TTP slowed TNF-α mRNA turnover, thereby increasing TNF-α protein expression. The SEM-Mb-induced decrease in cell viability and TNF-α upregulation were alleviated by abrogating the NOX4/SIRT3/ROS/p38 MAPK axis or ectopic expression of TTP. Taken together, our results demonstrated that the NOX4/SIRT3/p38 MAPK/TTP axis induces TNF-α-mediated apoptosis in U937 cells following SEM-Mb treatment. A pathway regulating p38 MAPK-mediated TNF-α expression also explains the cytotoxicity of SEM-Mb in the human leukemia cell lines HL-60, THP-1, K562, Jurkat, and ABT-199-resistant U937. Furthermore, these findings suggest that the carboxyl group-modified Mb is a potential structural template for the generation of tumoricidal proteins.

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