A Golgi-Targeted Platinum Complex Plays a Dual Role in Autophagy Regulation for Highly Efficient Cancer Therapy

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Autophagy regulation is a key strategy for cancer therapy.
• Golgi-autophagy (Golgiphagy) is an under-explored antitumor pathway.
• Targeting the Golgi apparatus offers a novel therapeutic avenue.

Purpose of the Study:

• To develop and evaluate a novel Golgi-targeted platinum (II) complex (Pt3) for cancer treatment.
• To investigate the mechanism of Pt3-induced anti-tumor effects.
• To explore the role of Golgi stress and autophagy regulation in Pt3's efficacy.

Main Methods:

• Synthesis and characterization of the Golgi-targeted platinum (II) complex Pt3.
• In vitro cytotoxicity assays comparing Pt3 to cisplatin in lung carcinoma cells.
• In vivo anti-tumor efficacy studies following intratumoral and tail vein administration.
• Analysis of Golgi structure, protein expression (GM130, GRASP65/55), and cellular processes (transport, glycosylation).
• Autophagy flux and apoptosis assays to elucidate the mechanism of action.

Main Results:

• Pt3 demonstrated significantly higher cytotoxicity (approx. 20x) against lung carcinoma compared to cisplatin.
• Intratumoral administration of Pt3 led to complete tumor elimination in vivo.
• Pt3 induced substantial Golgi stress, characterized by structural fragmentation and protein down-regulation.
• Pt3 triggered Golgiphagy but inhibited autophagosome-lysosome fusion, a dual role in autophagy.
• This dual regulation resulted in proteostasis loss and apoptotic cancer cell death.

Conclusions:

• Pt3 is the first Golgi-targeted platinum complex to induce Golgi stress-mediated dual-regulation of autophagic flux.
• Pt3 effectively leverages autophagy-apoptosis crosstalk for highly efficient cancer therapy.
• The novel mechanism offers a promising new strategy for treating lung carcinoma and potentially other cancers.