Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/Akt Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer.

Abstract

Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation are initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) treatment, but soon develop an acquired resistance. The treatment effect of EGFR-TKIs-resistant NSCLC patients still faces challenges. Cucurbitacin B (CuB), a triterpene hydrocarbon compound isolated from plants of various families and genera, elicits anticancer effects in a variety of cancer types. However, whether CuB is a viable treatment option for gefitinib-resistant (GR) NSCLC remains unclear. Here, we investigated the anticancer effects and underlying mechanisms of CuB. We report that CuB inhibited the growth and invasion of GR NSCLC cells and induced apoptosis. The inhibitory effect of CuB occurred through its promotion of the lysosomal degradation of EGFR and the downregulation of the cancerous inhibitor of protein phosphatase 2A/protein phosphatase 2A/Akt (CIP2A/PP2A/Akt) signaling axis. CuB and cisplatin synergistically inhibited tumor growth. A xenograft tumor model indicated that CuB inhibited tumor growth in vivo. Immunohistochemistry results further demonstrated that CuB decreased EGFR and CIP2A levels in vivo. These findings suggested that CuB could suppress the growth and invasion of GR NSCLC cells by inducing the lysosomal degradation of EGFR and by downregulating the CIP2A/PP2A/Akt signaling axis. Thus, CuB may be a new drug candidate for the treatment of GR NSCLC.

• Authors: Pengfei Liu, Yuchen Xiang, Xuewen Liu, Te Zhang, Rui Yang, Sen Chen, Li Xu, Qingqing Yu, Huzi Zhao, Liang Zhang, Ying Liu, Yuan Si
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 24 Issue 3 (Feb 12 2019) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 30759826 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Autoantigens
• CIP2A protein, human
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Protein Kinase Inhibitors
• Triterpenes
• cucurbitacin B
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• Protein Phosphatase 2
• Gefitinib

Topics

• A549 Cells
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autoantigens (metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• ErbB Receptors (metabolism)
• Female
• Gefitinib (pharmacology)
• Gene Expression Regulation, Neoplastic
• Humans
• Intracellular Signaling Peptides and Proteins
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Lysosomes (drug effects, metabolism)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Nude
• Protein Kinase Inhibitors (pharmacology)
• Protein Phosphatase 2 (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Triterpenes (pharmacology)