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Therapeutic targeting using tumor specific peptides inhibits long non-coding RNA HOTAIR activity in ovarian and
Ali R Özeş1, Yinu Wang2, Xingyue Zong2
1Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, IN, 47405, USA.
Abstract:
Long non-coding RNAs (lncRNAs) play key roles in human diseases, including cancer. Functional studies of the lncRNA HOTAIR (HOX transcript antisense RNA) provide compelling evidence for therapeutic targeting of HOTAIR in cancer, but targeting lncRNAs in vivo has proven to be difficult. In the current study, we describe a peptide nucleic acids (PNA)-based approach to block the ability of HOTAIR to interact with EZH2 and subsequently inhibit HOTAIR-EZH2 activity and resensitize resistant ovarian tumors to platinum. Treatment of HOTAIR-overexpressing ovarian and breast cancer cell lines with PNAs decreased invasion and increased chemotherapy sensitivity. Furthermore, the mechanism of action correlated with reduced nuclear factor-kappaB (NF-κB) activation and decreased expression of NF-κB target genes matrix metalloprotease 9 and interleukin 6. To deliver the anti-lncRNA to the acidic (pH approximately 6) tumor microenvironment, PNAs were conjugated to pH-low insertion peptide (pHLIP). Treatment of mice harboring platinum-resistant ovarian tumor xenografts with pHLIP-PNA constructs suppressed HOTAIR activity, reduced tumor formation and improved survival. This first report on pHLIP-PNA lncRNA targeting solid tumors in vivo suggests a novel cancer therapeutic approach.
Insights
Researchers developed a novel peptide nucleic acid (PNA) delivery system using pH-low insertion peptide (pHLIP) to target the long non-coding RNA HOTAIR in ovarian cancer. This approach resensitized tumors to chemotherapy and improved survival in preclinical models.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Delivery
Background:
- Long non-coding RNAs (lncRNAs) are implicated in human diseases, notably cancer.
- The lncRNA HOTAIR (HOX transcript antisense RNA) is a potential therapeutic target in cancer.
- In vivo targeting of lncRNAs remains a significant challenge in cancer therapy.
Purpose of the Study:
- To develop a peptide nucleic acid (PNA)-based strategy to inhibit HOTAIR-EZH2 interactions.
- To investigate the efficacy of this approach in resensitizing platinum-resistant ovarian tumors.
- To evaluate the in vivo delivery and therapeutic potential of PNA conjugates in solid tumors.
Main Methods:
- Utilized peptide nucleic acids (PNAs) to block HOTAIR-EZH2 interaction.
- Conjugated PNAs to pH-low insertion peptide (pHLIP) for tumor microenvironment delivery.
- Assessed PNA efficacy in vitro using ovarian and breast cancer cell lines.
- Evaluated pHLIP-PNA constructs in mice with platinum-resistant ovarian tumor xenografts.
Main Results:
- PNA treatment decreased cancer cell invasion and enhanced chemotherapy sensitivity.
- Mechanism involved reduced nuclear factor-kappaB (NF-κB) activation and target gene expression.
- pHLIP-PNA treatment suppressed HOTAIR activity in vivo.
- Tumor formation was reduced, and survival was improved in treated mice.
Conclusions:
- pHLIP-PNA conjugates represent a novel therapeutic approach for targeting lncRNAs in solid tumors.
- This strategy effectively inhibits HOTAIR activity and overcomes platinum resistance in ovarian cancer.
- The pH-responsive delivery system facilitates anti-lncRNA therapy in the tumor microenvironment.