Steroidal alkaloid solanidine impedes hypoxia-driven ATM phosphorylation to switch on anti-angiogenesis in lung adenocarcinoma
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Ankith Sherapura1, B M Siddesh1, Vikas H Malojirao2
1Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, 577203, Karnataka, India.
Purpose:
The declined oxygen tension in the cancer cell leads to the hypoxic adaptive response and favors establishment of tumor micro environment [TEM]. The complex TME consists of interwoven hypoxic HIF-1α and DNA damage repair ATM signaling. The ATM/HIF-1α phosphorylation switch on angiogenesis and abort apoptosis. Targeting this signaling nexus would be a novel therapeutic strategy for the treatment of cancer.
Background:
Steroidal alkaloid solanidine is known for varied pharmacological role but with less molecular evidences. Our earlier findings on solanidine proven its anti-neoplastic activity by inducing apoptosis in lung cancer. In continued research, efforts have been made to establish the underlying molecular signaling in induction of DNA damage in prevailing hypoxic TME.
Methods:
The solanidine induced DNA damage was assessed trough alkali COMET assay; signaling nexus and gene expression profile analysis through IB, qRT-PCR, Gelatin Zymography, IHC, IF and ELISA. Pathophysiological modulations assessed through tube formation, migration, invasion assays. Anti-angiogenic studies through CAM, rat aorta, matrigel assays and corneal neovascularization assay. Anti-tumor activity through in-vivo DLA ascites tumor model and LLC model.
Results:
The results postulates, inhibition of hypoxia driven DDR proteins pATMser1981/pHIF-1αser696 by solanidine induces anti-angiogenesis. Systematic study of both non-tumorigenic and tumorigenic models in-vitro as well as in-vivo experimental system revealed the angio-regression mediated anticancer effect in lung cancer. These effects are due to the impeded expression of angiogenic mediators such as VEGF, MMP2&9 and inflammatory cytokines IL6 and TNFα to induce pathophysiological changes CONCLUSION: The study establishes new role of solanidine by targeting ATM/HIF-1α signaling to induce anti-angiogenesis for the first time. The study highlights the potentiality of plant based phytomedicine solanidine which can targets the multiple hallmarks of cancer by targeting interwoven signaling crosstalk. Such an approach through solanidine necessary to counteract heterogeneous complexity of cancer which could be nearly translated into drug.
Insights
Solanidine inhibits cancer cell growth by targeting the ATM/HIF-1α signaling pathway, thereby reducing DNA damage and angiogenesis. This plant-derived compound shows potential as a novel anti-cancer therapy by disrupting key tumor microenvironment mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hypoxia, a hallmark of the tumor microenvironment (TME), triggers adaptive responses involving ATM and HIF-1α signaling.
- Solanidine, a steroidal alkaloid, has demonstrated anti-neoplastic effects, including apoptosis induction in lung cancer.
- Previous research indicated solanidine's anti-cancer activity; this study investigates its molecular mechanisms within the hypoxic TME.
Purpose of the Study:
- To elucidate the molecular signaling pathways targeted by solanidine in inducing DNA damage within a hypoxic TME.
- To investigate the anti-angiogenic and anti-tumor effects of solanidine by targeting the ATM/HIF-1α signaling nexus.
- To establish solanidine as a potential therapeutic agent against lung cancer by modulating key cancer hallmarks.
Main Methods:
- DNA damage assessed via alkali COMET assay; signaling pathway analysis using Western blot, qRT-PCR, IHC, and ELISA.
- Gene expression profiling and protein analysis to determine the impact on ATM/HIF-1α signaling.
- In vitro and in vivo assays evaluated angiogenesis, cell migration, invasion, and anti-tumor activity.
Main Results:
- Solanidine effectively inhibits hypoxia-driven DDR proteins pATM and pHIF-1α, leading to significant anti-angiogenesis.
- In vitro and in vivo studies confirmed solanidine's angio-regressive and anti-cancer effects in lung cancer models.
- Solanidine impedes the expression of angiogenic mediators (VEGF, MMP2&9) and inflammatory cytokines (IL6, TNFα), inducing crucial pathophysiological changes.
Conclusions:
- This study establishes a novel role for solanidine in targeting the ATM/HIF-1α signaling pathway to induce anti-angiogenesis in cancer.
- Solanidine, a plant-based phytomedicine, demonstrates potential in targeting multiple cancer hallmarks through interwoven signaling crosstalk.
- The findings suggest solanidine's therapeutic potential for combating the complex and heterogeneous nature of cancer, paving the way for drug development.
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