Browsing by Author "Cao, Li"

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    BCL-XL Protects ASS1-Deficient Cancers from Arginine Starvation-Induced Apoptosis
    (American Association for Cancer Research, 2025) Panda, Prashanta Kumar; Paschoalini Mafra, Ana Carolina; Bastos, Alliny C. S.; Cao, Li; Bonet, Maria Serra; Brashears, Caitlyn B.; Chen, Ethan Yang; Benedict-Hamilton, Heather M.; Ehrhardt, William; Bomalaski, John; Dehner, Carina; Rogers, Leonard C.; Oyama, Toshinao; Van Tine, Brian A.; Pathology and Laboratory Medicine, School of Medicine
    Purpose: Argininosuccinate synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, such as PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis. Experimental design: The effects of ADI-PEG20 on cell-cycle regulation, apoptosis, and BCL-XL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions among BCL-XL, BAX, and BAK. In vitro synergy was determined, and in vivo efficacy was modeled. Results: Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell-cycle progression but did not induce significant cell death. BCL-XL was found to bind to BAX and BAK, preventing the initiation of apoptosis despite arginine starvation. Inhibition of BCL-XL allowed proapoptotic BAX and BAK to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo. Conclusions: The study identifies BCL-XL as a key factor limiting the efficacy of arginine starvation therapies. Combining BCL-XL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in phase 1 clinical trials for ASS1-deficient cancers.
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    Endurance exercise accelerates myocardial tissue oxygenation recovery and reduces ischemia reperfusion injury in mice
    (PLoS, 2014-12-04) Li, Yuanjing; Cai, Ming; Cao, Li; Qin, Xing; Zheng, Tiantian; Xu, Xiaohua; Sandvick, Taylor M.; Hutchinson, Kirk; Wold, Loren E.; Hu, Keli; Sun, Qinghua; Thomas, D. Paul; Ren, Ju; He, Guanglong; Department of Medicine, IU School of Medicine
    Exercise training offers cardioprotection against ischemia and reperfusion (I/R) injury. However, few essential signals have been identified to underscore the protection from injury. In the present study, we hypothesized that exercise-induced acceleration of myocardial tissue oxygenation recovery contributes to this protection. C57BL/6 mice (4 weeks old) were trained on treadmills for 45 min/day at a treading rate of 15 m/min for 8 weeks. At the end of 8-week exercise training, mice underwent 30-min left anterior descending coronary artery occlusion followed by 60-min or 24-h reperfusion. Electron paramagnetic resonance oximetry was performed to measure myocardial tissue oxygenation. Western immunoblotting analyses, gene transfection, and myography were examined. The oximetry study demonstrated that exercise markedly shortened myocardial tissue oxygenation recovery time following reperfusion. Exercise training up-regulated Kir6.1 protein expression (a subunit of ATP-sensitive K(+)channel on vascular smooth muscle cells, VSMC sarc-K(ATP)) and protected the heart from I/R injury. In vivo gene transfer of dominant negative Kir6.1AAA prolonged the recovery time and enlarged infarct size. In addition, transfection of Kir6.1AAA increased the stiffness and reduced the relaxation capacity in the vasculature. Together, our study demonstrated that exercise training up-regulated Kir6.1, improved tissue oxygenation recovery, and protected the heart against I/R injury. This exercise-induced cardioprotective mechanism may provide a potential therapeutic intervention targeting VSMC sarc-K(ATP) channels and reperfusion recovery.