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SRT1720 inhibits bladder cancer cell progression by impairing autophagic flux
Lanlan Li1, Shengjun Fu1, Jianliang Wang2
1Institute of Urology, Key Laboratory of Urological Disease in Gansu Province, Clinical Research Center for Urology in Gansu Province, Lanzhou University Second Hospital, No. 82 Cuiyingmen, Lanzhou 730030, Gansu, China.
Abstract:
Bladder cancer (BC) is the most common cancer of the urinary tract, with poor survival, high recurrence rates, and lacking of targeted drugs. In this study, we constructed a library to screen compounds inhibiting bladder cancer cells growth. Among them, SRT1720 was identified to inhibit bladder cancer cell proliferation in vitro and in vivo. SRT1720 treatment also suppressed bladder cancer cells migration, invasion and induced apoptosis. Mechanism studies shown that SRT1720 promoted autophagosomes accumulation by inducing early-stage autophagy but disturbed the late-stage of autophagy by blocking fusion of autophagosomes and lysosomes. SRT1720 appears to induce autophagy related proteins expression and alter autophagy-related proteins acetylation to impede the autophagy flux. LAMP2, an important lysosomal associated membrane protein, may mediate SRT1720-inhibited autophagy flux as SRT1720 treatment significantly deacetylated LAMP2 which may influence its activity. Taken together, our results demonstrated that SRT1720 mediated apoptosis and autophagy flux inhibition may be a novel therapeutic strategy for bladder cancer treatment.
Insights
SRT1720 inhibits bladder cancer growth by inducing apoptosis and blocking autophagy flux. This compound shows promise as a novel therapeutic strategy for bladder cancer treatment, targeting key cellular processes.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Bladder cancer (BC) presents significant challenges with poor survival and high recurrence rates.
- Current treatments lack targeted drug options for bladder cancer.
- Identifying novel therapeutic agents is crucial for improving patient outcomes.
Purpose of the Study:
- To screen compounds for inhibiting bladder cancer cell growth.
- To investigate the therapeutic potential of SRT1720 in bladder cancer.
- To elucidate the molecular mechanisms underlying SRT1720's effects on bladder cancer cells.
Main Methods:
- Compound library screening to identify inhibitors of bladder cancer cell growth.
- In vitro and in vivo studies to evaluate SRT1720's efficacy.
- Analysis of apoptosis, migration, invasion, and autophagy pathways.
- Investigation of protein acetylation, particularly of LAMP2, in response to SRT1720.
Main Results:
- SRT1720 demonstrated significant inhibition of bladder cancer cell proliferation, migration, and invasion.
- SRT1720 induced apoptosis in bladder cancer cells.
- SRT1720 promoted early-stage autophagy but inhibited late-stage autophagy by blocking autophagosome-lysosome fusion.
- SRT1720 altered autophagy-related protein expression and acetylation, including deacetylation of LAMP2.
Conclusions:
- SRT1720 exhibits potent anti-cancer effects in bladder cancer models.
- Inhibition of autophagy flux by SRT1720 is a key mechanism of its action.
- SRT1720-induced apoptosis and autophagy flux inhibition represent a potential novel therapeutic strategy for bladder cancer.
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