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D-M159 Synergistically Induces Apoptosis in HeLa Cells Through Endoplasmic Reticulum Stress and Mitochondrial

Yuanyuan Li1,2, Dingding Li1, Zonghan Jiang2

  • 1Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Pharmacy, Hunan Normal University, Changsha 410013, China.

International Journal of Molecular Sciences
|April 17, 2025
PubMed

Insights

D-M159, a novel peptide, effectively induces cancer cell death (apoptosis) in HeLa cells, particularly under starvation conditions. This peptide triggers cell death through endoplasmic reticulum stress and mitochondrial dysfunction, showing potential as an anticancer agent.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Pore-forming peptides offer potential as antimicrobial and anticancer agents due to selective membrane interaction and biodegradability.
  • Previous research identified peptide M159 with selective liposome permeabilization and no mammalian cell toxicity.
  • The D-type variant, D-M159, was investigated for its anticancer properties.

Purpose of the Study:

  • To explore the anticancer mechanism of D-M159 in HeLa cells, focusing on its cytotoxicity, cellular uptake, and apoptotic pathways.
  • To investigate the role of calcium dynamics and mitochondrial function in D-M159-induced cell death.
  • To elucidate the involvement of endoplasmic reticulum stress and mitochondrial dysfunction in D-M159's anticancer activity.

Main Methods:

  • Cytotoxicity, intracellular uptake, and apoptosis were assessed using flow cytometry, confocal microscopy, and Western blot.
  • Calcium dynamics and mitochondrial function were evaluated through specific labeling and functional assays.
  • Key proteins involved in endoplasmic reticulum stress (ATF6, p-IRE1, PERK, GRP78, CHOP) and apoptosis (Bax, Bcl-2, Caspase-9, Caspase-3) were analyzed.

Main Results:

  • D-M159 demonstrated starvation-dependent, dose-responsive cytotoxicity, inducing apoptosis in HeLa cells.
  • Cellular uptake occurred via caveolin-dependent and caveolae-dependent endocytosis.
  • D-M159 induced endoplasmic reticulum stress and mitochondrial dysfunction, characterized by calcium overload, decreased mitochondrial membrane potential, increased ROS, and altered apoptotic protein expression.

Conclusions:

  • D-M159 synergistically induces apoptosis in starved HeLa cells via combined endoplasmic reticulum stress and mitochondrial dysfunction.
  • The findings highlight D-M159's potential as a novel anticancer therapeutic agent.
  • Understanding the mechanism of D-M159 provides insights into targeted cancer therapy development.
Keywords:
D-M159apoptosisendoplasmic reticulum stressmitochondrial dysfunctionpeptide

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