A Novel Modulator of Resistance for Oxaliplatin-Based Therapy for Colorectal Cancer: The ESCRT Family Member VPS4A

• Published in: Cells (Basel, Switzerland) Vol. 14; no. 12; p. 929
• Main Authors: Abdelrazik, Noha M., Patel, Anjana, Conn, Andrew, Sutton, Christopher W., Kantamneni, Sriharsha, Shnyder, Steven D.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.06.2025; MDPI
• Subjects: Antibodies; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; ATPases Associated with Diverse Cellular Activities - metabolism; Biomarkers; Cancer; Cancer therapies; Care and treatment; Cell Line, Tumor; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Drinking water; Drug resistance; Drug Resistance, Neoplasm - drug effects; Electric properties; endosomal sorting complex required for transport (ESCRT) protein family; Endosomal Sorting Complexes Required for Transport - antagonists & inhibitors; Endosomal Sorting Complexes Required for Transport - genetics; Endosomal Sorting Complexes Required for Transport - metabolism; Epithelium; Ethylenediaminetetraacetic acid; Health aspects; Humans; Immunoblotting; Immunohistochemistry; Laboratories; Molecules; Oxaliplatin; Oxaliplatin - pharmacology; Oxaliplatin - therapeutic use; Physiology; Protein expression; Protein transport; Proteins; RNA sequencing; Sequence analysis; vacuolar protein sorting-associated protein A4; Vacuolar Proton-Translocating ATPases; United Kingdom; United Kingdom > UK; oxaliplatin; colorectal cancer; drug resistance; vacuolar protein sorting-associated protein A4; endosomal sorting complex required for transport (ESCRT) protein family
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells14120929

Drug resistance is still one of the main challenges for the treatment of colorectal cancer (CRC). Whilst some resistance mechanisms are well known, from the static therapy success rate, clearly, still much is undiscovered. Intracellular transport mechanisms have attracted attention as having a possible role in drug resistance, and here, the Endosomal Sorting Complex Required for Transport (ESCRT) protein family is studied as a source of drug resistance modulation using human CRC cell lines and clinical material. From an initial screening of ESCRT proteins in a panel of 10 CRC wild-type cell lines using immunoblotting, Vacuolar Protein Sorting-Associated Protein A4 (VPS4A) was identified as being consistently highly expressed, and it was selected for further investigation. Immunohistopathological evaluation in a small panel of CRC patient samples demonstrated high expression in the tumor epithelium compared to normal intestinal epithelium. The knockdown of VPS4A resulted in enhanced sensitivity of cells to oxaliplatin, and it was subsequently seen that oxaliplatin-resistant sublines had significantly higher VPS4A expression than their wild-type variants. In addition, it was demonstrated that a small molecule inhibitor of VPS4A, aloperine, could interact synergistically with oxaliplatin to enhance its sensitivity in an oxaliplatin-resistant cell line. We hypothesize from initial RNA sequencing analysis that the mechanism of action of VPS4A modulation is through depleting levels of the drug efflux transporter MRP2 in the cell, preventing oxaliplatin egress and increasing cell exposure to the drug. The evidence presented here thus indicates that ESCRT machinery, specifically VPS4A, may act as a modulator of oxaliplatin resistance in CRC.