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Enhanced apoptotic effects by downregulating Mcl-1: evidence for the improvement of photodynamic therapy with
Jiaxing Song1, Qun Chen, Da Xing
1MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
Abstract:
Tumor cells exposed to sub-lethal photodynamic therapy (PDT) cause cellular rescue responses that lead to resistance to the therapy, including expression of angiogenic factors and survival molecules. However, the mechanisms contributing to the resistance are yet to be fully understood. Here, we show for the first time that Mcl-1, an anti-apoptotic protein, plays an important role in protecting cells from PDT-induced apoptosis. In contrast to the reduction in the anti-apoptotic proteins Bcl-2 and Bcl-xl, sub-lethal PDT induces an increase in Mcl-1 expression. Silencing Mcl-1 sensitizes tumor cells to PDT-induced apoptosis, and ectopic expression of Mcl-1 significantly delays Bax translocation to mitochondria and inhibits caspase-3 activity following PDT. Mcl-1 expression is associated closely with activated AKT signaling following PDT. AKT can regulate Mcl-1 expression through GSK-3β and NF-κB at the protein and transcriptional levels, respectively. Inhibition of AKT by Wortmannin or siRNA significantly reduces the levels of Mcl-1 mRNA and protein and enhances PDT-induced apoptosis. Treatment with Celecoxib, a non-steroidal anti-inflammatory drug (NSAID), is shown to downregulate Mcl-1 expression, and enhances PDT-induced apoptosis both in vitro and in vivo. This down-regulation is closely related to the inhibition effect of Celecoxib on the AKT/GSK-3β pathway, and was blocked upon addition of GSK-3β inhibitor LiCl or the proteasome inhibitor MG132. These results suggest that Mcl-1 is a potential target for improving the antitumor efficiency of PDT. A loss in Mcl-1 by inhibiting AKT promotes PDT-induced apoptosis through the mitochondrial pathway. This also provides a novel rationale for utilizing Celecoxib to improve the efficacy of PDT.
Insights
Sub-lethal photodynamic therapy (PDT) resistance is linked to Mcl-1, an anti-apoptotic protein. Inhibiting Mcl-1 enhances PDT
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Sub-lethal photodynamic therapy (PDT) can induce tumor cell resistance through survival mechanisms.
- The precise molecular pathways driving PDT resistance remain incompletely understood.
- Mcl-1, an anti-apoptotic protein, has emerged as a potential regulator of cell survival.
Purpose of the Study:
- To investigate the role of Mcl-1 in mediating resistance to PDT-induced apoptosis.
- To elucidate the signaling pathways regulating Mcl-1 expression in response to PDT.
- To evaluate the potential of targeting Mcl-1 to enhance PDT efficacy.
Main Methods:
- Gene silencing (siRNA) and ectopic expression of Mcl-1 in tumor cells.
- Assessment of apoptosis markers (Bax translocation, caspase-3 activity) post-PDT.
- Analysis of AKT signaling pathway activation and its regulation of Mcl-1.
- In vitro and in vivo studies using Celecoxib to modulate Mcl-1 and PDT response.
Main Results:
- Sub-lethal PDT increases Mcl-1 expression, conferring resistance to apoptosis.
- Mcl-1 silencing sensitizes tumor cells to PDT, while its overexpression delays apoptosis.
- AKT signaling pathway activation positively regulates Mcl-1 expression.
- Inhibition of AKT or treatment with Celecoxib downregulates Mcl-1 and enhances PDT-induced apoptosis.
Conclusions:
- Mcl-1 is a key mediator of tumor cell resistance to PDT.
- Targeting Mcl-1, potentially via AKT inhibition or NSAIDs like Celecoxib, can overcome PDT resistance.
- Mcl-1 represents a promising therapeutic target for improving the efficacy of photodynamic therapy.
