CHMP4C Disruption Sensitizes the Human Lung Cancer Cells to Irradiation

Abstract

Human lung cancer is highly invasive and the most malignant among human tumors. Adenocarcinoma as a specific type of non-small cell lung cancer occurs with high frequency and is also highly resistant to radiation therapy. Thus, how to avoid radiation resistance and improve radiotherapy effectiveness is a crucial question. In the present study, human lung cancer A549 and H1299 cells were irradiated using γ-rays from a Co60 irradiator. Protein expression was detected by Western blotting. Cell cycle and apoptosis were measured by flow cytometry. Surviving fraction was determined by colony formation assay. γH2AX and 53BP1 foci formation were examined by fluorescence microscopy. In the results, we show that CHMP4C, a subunit of Endosomal sorting complex-III (ESCRT-III), is involved in radiation-induced cellular response. Radiation-induced Aurora B expression enhances CHMP4C phosphorylation in non-small cell lung cancer (NSCLC) cells, maintaining cell cycle check-point and cellular viability as well as resisting apoptosis. CHMP4C depletion enhances cellular sensitivity to radiation, delays S-phase of cell cycle and reduces ionizing radiation (IR)-induced γH2AX foci formation. We found that Aurora B targets CHMP4C and inhibition of Aurora B exhibits similar effects with silencing of CHMP4C in radioresistance. We also confirm that CHMP4C phosphorylation is elevated after IR both in p53-positive and-negative cells, indicating that the close correlation between CHMP4C and Aurora B signaling pathway in mediating radiation resistance is not p53 dependent. Together, our work establishes a new function of CHMP4C in radiation resistance, which will offer a potential strategy for non-small cell lung cancer by disrupting CHMP4C.

Prognostic significance of an autophagy‑related long non‑coding RNA signature in patients with oral and oropharyngeal squamous cell carcinoma

“…They are components of the endosomal sorting complex required for transport III involved in the formation of endocytic multivesicular bodies ( 42 ). CHMP4A expression is associated with the recurrence of ovarian cancer ( 43 ), whereas CHMP4C regulates radiation resistance in non-small cell lung cancer ( 44 ).…”

Proteomic analysis of urinary extracellular vesicles from high Gleason score prostate cancer

“…CHMP4A, CHMP4C, and CHMP2B belong to the chromatin-modifying protein/charged multivesicular body protein family and are components of ESCRT-III (endosomal sorting complex required for transport III) involved in the formation of endocytic multivesicular bodies 39 . CHMP4A expression is associated with the recurrent ovarian cancer 40 , and CHMP4C plays roles in radiation resistance in non-small cell lung cancer 41 . GRN, AMBP, CHMP4A, CHMP4C, and CHMP2 may play important roles in aggressive prostate cancer and may be potential targets of treatment.…”

A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability

“…These cells may nevertheless remain sensitive to further perturbations of chromosome segregation or DNA-damaging agents, and this sensitivity could, in principle, be exploited therapeutically. In this regard, it is noteworthy that CHMP4C depletion increases the effectiveness of irradiation-induced apoptosis in human lung cancer cells ( 54 ) and that many common chemotherapeutic drugs, such as paclitaxel, act, at least in part, by increasing chromosome missegregation ( 40 ). Hence, we speculate that such chemotherapeutics may be particularly effective in patients who carry the CHMP4C T232 allele.…”