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Published on: October 4, 2022
Methylseleninic acid suppresses pancreatic cancer growth involving multiple pathways
Lei Wang1, Hongbo Hu, Zhe Wang
1a Hormel Institute , University of Minnesota , Austin , Minnesota , USA.
Abstract:
As a potential novel agent for treating pancreatic cancer, methylseleninic acid (MSeA) was evaluated in cell culture and xenograft models. Results showed that MSeA induced G1 cell cycle arrest and apoptosis in a majority of human and mouse pancreatic cancer cell lines, but G2 arrest in human PANC-1 and PANC-28 cell lines. In contrast to our previous finding in human prostate cancer LNCaP cells having a lack of P53 activation by MSeA, induction of G2 arrest in PANC-1 cells was accompanied by increased mutant P53 Ser15 phosphorylation, upregulation of P53-targets P21Cip1 and GADD45 and G2 checkpoint kinase (Chk2) activation, suggestive of DNA damage responses. A rapid inhibition of AKT phosphorylation was followed by reduced mTOR signaling and increased autophagy in PANC-1 cells attenuating caspase-mediated apoptosis execution. Furthermore, daily oral treatment with MSeA (3 mg Se/kg body weight) significantly suppressed growth of subcutaneously inoculated PANC-1 xenograft in SCID mice. Immunohistochemical analyses detected increased p-Ser15 P53, P21Cip1, pS139-H2AX (DNA damage responses), and caspase-3 cleavage and decreased pSer473AKT and Ki67 proliferative index and reduced intratumor vascular density in MSeA-treated xenograft. These results provide impetus for further research of MSeA in the therapy and/or chemoprevention of pancreatic cancer.
Insights
Methylseleninic acid (MSeA) shows promise for pancreatic cancer treatment. It effectively halts cancer cell growth and triggers apoptosis in models, suggesting potential for therapy and prevention.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Pancreatic cancer remains a significant health challenge with limited effective treatments.
- Methylseleninic acid (MSeA) is being investigated as a novel therapeutic agent.
- Understanding MSeA's mechanism of action in pancreatic cancer is crucial for its clinical application.
Purpose of the Study:
- To evaluate the efficacy of methylseleninic acid (MSeA) as a potential treatment for pancreatic cancer.
- To investigate the cellular and molecular mechanisms underlying MSeA's effects in pancreatic cancer models.
- To assess MSeA's therapeutic potential in both in vitro and in vivo pancreatic cancer models.
Main Methods:
- Cell cycle analysis (G1/G2 arrest) and apoptosis assays were performed on human and mouse pancreatic cancer cell lines.
- Western blotting and immunohistochemistry were used to assess protein expression, phosphorylation, and signaling pathways (P53, AKT, mTOR, DNA damage markers).
- In vivo efficacy was evaluated using PANC-1 xenograft models in SCID mice treated with MSeA.
Main Results:
- MSeA induced G1 cell cycle arrest and apoptosis in most pancreatic cancer cell lines, with G2 arrest observed in PANC-1 and PANC-28 cells.
- In PANC-1 cells, MSeA triggered DNA damage responses, including P53 activation, P21Cip1 and GADD45 upregulation, and Chk2 activation.
- MSeA treatment significantly suppressed PANC-1 xenograft growth, reduced tumor vascularity, and modulated key cancer-related signaling pathways in vivo.
Conclusions:
- MSeA demonstrates significant anti-cancer activity against pancreatic cancer cells through cell cycle arrest, apoptosis induction, and DNA damage response pathways.
- MSeA effectively inhibits tumor growth and angiogenesis in vivo, supporting its potential as a therapeutic agent or chemopreventive strategy for pancreatic cancer.
- Further research into MSeA for pancreatic cancer therapy and chemoprevention is warranted based on these promising preclinical findings.
