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Published on: July 25, 2022
JNK2 silencing and caspase-9 activation by hyperosmotic polymer inhibits tumor progression
Pankaj Garg1, Shambhavi Pandey1, Seonwoo Hoon1
1Department of Biosystems & Biomaterials Science and Engineering, Seoul National University, Seoul 151-921, Republic of Korea.
Abstract:
c-Jun N-terminal kinase 2 (JNK2) is primarily responsible for the oncogenic transformation of the transcription factor c-Jun. Expression of the proto-oncogene c-Jun progresses the cell cycle from G1 to S phase, but when its expression becomes awry it leads to uncontrolled proliferation and angiogenesis. Delivering a JNK2 siRNA (siJNK2) in tumor tissue was anticipated to reverse the condition with subsequent onset of apoptosis which predominantly requires an efficient delivering system capable of penetrating through the compact tumor mass. In the present study, it was demonstrated that polymannitol-based vector (PMGT) with inherent hyperosmotic properties was able to penetrate through and deliver the siJNK2 in the subcutaneous tumor of xenograft mice. Hyperosmotic activity of polymannitol was shown to account for the enhanced therapeutic delivery both in vitro and in vivo because of the induction of cyclooxygenase-2 (COX-2) which stimulates caveolin-1 for caveolae-mediated endocytosis of the polyplexes. Further suppression of JNK2 and hence c-Jun expression led to the activation of caspase-9 to induce apoptosis and inhibition of tumor growth in xenograft mice model. The study exemplifies PMGT as an efficient vector for delivering therapeutic molecules in compact tumor tissue and suppression of JNK2 introduces a strategy to inhibit tumor progression.
Insights
Polymannitol-based vectors effectively deliver JNK2 siRNA into tumors, inhibiting cancer growth. This approach suppresses c-Jun, inducing apoptosis and offering a new strategy for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- c-Jun N-terminal kinase 2 (JNK2) drives oncogenic transformation of c-Jun, promoting uncontrolled cell proliferation and angiogenesis.
- Efficient delivery of therapeutic molecules, like JNK2 siRNA (siJNK2), into compact tumor masses is crucial for cancer treatment.
Purpose of the Study:
- To evaluate the efficacy of a polymannitol-based vector (PMGT) for delivering siJNK2 into subcutaneous tumors.
- To investigate the mechanism of PMGT-mediated delivery and its impact on tumor growth inhibition.
Main Methods:
- PMGT was used to deliver siJNK2 into subcutaneous tumors in xenograft mice.
- In vitro and in vivo studies assessed the hyperosmotic activity of PMGT and its effect on therapeutic delivery.
- The study analyzed the induction of cyclooxygenase-2 (COX-2), caveolin-1, and caspase-9 activation.
Main Results:
- PMGT successfully penetrated compact tumor tissue and delivered siJNK2.
- The hyperosmotic properties of PMGT enhanced therapeutic delivery by inducing COX-2 and caveolin-1-mediated endocytosis.
- Suppression of JNK2 and c-Jun led to caspase-9 activation, apoptosis, and significant tumor growth inhibition.
Conclusions:
- PMGT serves as an efficient vector for delivering therapeutic molecules into solid tumors.
- JNK2 suppression via siJNK2 delivery presents a viable strategy for inhibiting tumor progression and inducing apoptosis.
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