Albumin conjugation promotes arsenic trioxide transport through alkaline phosphatase-associated transcytosis in MUC4 wildtype pancreatic cancer cells.

Abstract

Pancreatic cancer (PC) has a poor prognosis due to chemotherapy resistance and unfavorable drug transportation. Albumin conjugates are commonly used as drug carriers to overcome these obstacles. However, membrane-bound glycoprotein mucin 4 (MUC4) has emerged as a promising biomarker among the genetic mutations affecting albumin conjugates therapeutic window. Human serum albumin-conjugated arsenic trioxide (HSA-ATO) has shown potential in treating solid tumors but is limited in PC therapy due to unclear targets and mechanisms. This study investigated the transport mechanisms and therapeutic efficacy of HSA-ATO in PC cells with different MUC4 mutation statuses. Results revealed improved penetration of ATO into PC tumors through conjugated with HSA. However, MUC4 mutation significantly affected treatment sensitivity and HSA-ATO uptake both in vitro and in vivo. Mutant MUC4 cells exhibited over ten times higher IC50 for HSA-ATO and approximately half the uptake compared to wildtype cells. Further research demonstrated that ALPL activation by HSA-ATO enhanced transcytosis in wildtype MUC4 PC cells but not in mutant MUC4 cells, leading to impaired uptake and weaker antitumor effects. Reprogramming the transport process holds potential for enhancing albumin conjugate efficacy in PC patients with different MUC4 mutation statuses, paving the way for stratified treatment using these delivery vehicles.

• Authors: Kaidi Chen, Xiao Cheng, Shuai Xue, Junyan Chen, Xu Zhang, Yuwei Qi, Rong Chen, Yan Zhang, Hangjie Wang, Wei Li, Guilin Cheng, Ye Huang, Yang Xiong, Liping Chen, Chaofeng Mu, Mancang Gu
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 257 Issue Pt 2 Pg. 128756 (Feb 2024) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 38092098 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier B.V.

Chemical References

• Arsenic Trioxide
• Alkaline Phosphatase
• Mucin-4
• Serum Albumin, Human
• MUC4 protein, human

Topics

• Humans
• Arsenic Trioxide (pharmacology, therapeutic use)
• Alkaline Phosphatase
• Mucin-4 (genetics, metabolism)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Serum Albumin, Human (therapeutic use)
• Transcytosis
• Cell Line, Tumor