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Combinatorial Anti-Cancer Effect of Polypurine Reverse Hoogsteen Hairpins against KRAS and MYC Targeting in Prostate
Simonas Valiuska1,2, Kayla K Elder3, Steven J McKay3
1Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona (UB), 08028 Barcelona, Spain.
Abstract:
Introduction: KRAS and MYC are proto-oncogenes that are strictly regulated in healthy cells that have key roles in several processes such as cell growth, proliferation, differentiation, or apoptosis. These genes are tightly interconnected, and their dysregulation can lead to cancer progression. We previously individually targeted these oncogenes using Polypurine Reverse Hoogsteen (PPRH) hairpins, mostly targeting the complementary strand of G-quadruplex-forming sequences. We validated them in vitro in different cancer cell lines with deregulated KRAS and/or MYC. In this work we focused on our understanding of the cooperative dynamics between these oncogenes, by investigating the combined impact of PPRHs targeting KRAS and MYC in pancreatic and prostate cancer cells. Results: The combinations had a modulatory impact on the expression of both oncogenes, with transcriptional and translational downregulation occurring five days post-treatment. Out of the four tested PPRHs, MYC-targeting PPRHs, especially HpMYC-G4-PR-C directed against the promoter, showed a greater cytotoxic and expression modulation effect. When both KRAS- and MYC-targeting PPRHs were applied in combination, a synergistic reduction in cell viability was observed. Conclusion: The simultaneous targeting of KRAS and MYC demonstrates efficacy in gene modulation, thus in decreasing cell proliferation and viability.
Insights
Targeting KRAS and MYC proto-oncogenes with Polypurine Reverse Hoogsteen (PPRH) hairpins synergistically reduced cancer cell viability. This dual gene modulation approach effectively decreased cell proliferation and expression of these key cancer-driving genes.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- KRAS and MYC are proto-oncogenes crucial for cell growth and proliferation.
- Dysregulation of KRAS and MYC is linked to cancer progression.
- Previous studies individually targeted these oncogenes using Polypurine Reverse Hoogsteen (PPRH) hairpins.
Purpose of the Study:
- To investigate the cooperative dynamics between KRAS and MYC.
- To evaluate the combined impact of PPRHs targeting both KRAS and MYC in pancreatic and prostate cancer cells.
Main Methods:
- Utilized Polypurine Reverse Hoogsteen (PPRH) hairpins to target KRAS and MYC oncogenes.
- Assessed transcriptional and translational modulation of oncogenes.
- Evaluated cell viability and cytotoxicity in cancer cell lines.
Main Results:
- Combined PPRH treatment modulated the expression of both KRAS and MYC, leading to downregulation.
- MYC-targeting PPRHs, particularly HpMYC-G4-PR-C, showed significant cytotoxic and expression modulation effects.
- Synergistic reduction in cancer cell viability was observed when both KRAS- and MYC-targeting PPRHs were applied concurrently.
Conclusions:
- Simultaneous targeting of KRAS and MYC with PPRHs is an effective strategy for gene modulation.
- This combined approach demonstrates efficacy in decreasing cancer cell proliferation and viability.
- The findings support the potential of dual oncogene targeting in cancer therapy.
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