Evaluating the immunoproteasome as a potential therapeutic target in cisplatin-resistant small cell and non-small cell lung cancer

Abstract

We evaluated the expression of proteasome subunits to assess whether the proteasome could be a therapeutic target in cisplatin-resistant lung cancer cells.Methods: Cisplatin-resistant (CR) variants were established from three non-small cell lung cancer (NSCLC) cell lines (A549, H1299, and H1975) and two small cell lung cancer (SCLC) cell lines (SBC3 and SBC5). The expression of proteasome subunits, the sensitivity to immunoproteasome inhibitors, and 20S proteasomal proteolytic activity were examined in the CR variants of the lung cancer cell lines.Results: All five CR cell lines highly expressed one or both of the immunoproteasome subunit genes, PSMB8 and PSMB9, while no clear trend was observed in the expression of constitutive proteasome subunits. The CR cells expressed significantly higher levels of PSMB8 and PSMB9 proteins as well. The CR variants of the H1299 and SBC3 cell lines were more sensitive to immunoproteasome inhibitors and had significantly more proteasomal proteolytic activity than their parental counterparts. Conclusions:The immunoproteasome may be an effective therapeutic target in a subset of CR lung cancers. Proteasomal proteolytic activity may be a predictive marker for the efficacy of immunoproteasome inhibitors in cisplatin-resistant SCLC and NSCLC.

Proteomic analysis to identification of hypoxia related markers in spinal tuberculosis: a study based on weighted gene co-expression network analysis and machine learning

“…Tetsuaki Shoji et al found that in cisplatin-resistant lung cancer cell line models, the transcription levels of PSMB8 and PSMB9 were highly expressed, and the protein expression levels were also significantly increased. After treatment with immunoproteasome inhibitors, it was found that immunoproteasomes may be an effective therapeutic target for some cisplatin-resistant lung cancers [ 47 ]. STAT1 is a signal transducer and activator of transcription 1, a member of the STAT protein family [ 48 ].…”

Antibody dependent cell-mediated cytotoxicity selection pressure induces diverse mechanisms of resistance

“…The immunoproteasome is an isoform of the constitutive 20S proteasome that becomes expressed when cells are stressed or in response to interferon-gamma and has recently become an attractive therapeutic target in some solid tumors. 46 , 47 We observed protein expression increases in all three immunoproteasome subunits (PSMB8, PSMB9, and PSMB10) by each ADCC-resistant cell line ( Figure 6a ). These increases in subunit expression resulted in significant upregulation of immunoproteasome protein cleavage activity which could be inhibited by the irreversible immunoproteasome-specific compound ONX-0914 ( Figure 6b ).…”

The Functional and Mechanistic Roles of Immunoproteasome Subunits in Cancer

“…Treatment of cisplatin-resistant tumor cells with proteasome inhibitors led to apoptosis induction, cell cycle arrest, and mitotic catastrophe. The authors propose that upregulation of immunoproteasome expression was a response to circumvent the cellular stress induced by cisplatin treatment [ 158 ]. Sensitivity to proteasome inhibitors by tumor cells was found to be associated with immunoproteasome subunit expression.…”

“…The regulation of catalytic βi-subunits in cancer is brought about by several mechanisms. As described, NFκB, mTOR, and STAT1 have been shown to regulate the expression of PSMB8 in colon and lung cancer [ 154 , 157 , 158 ]. In acute promyelocytic leukemia (APL), the fusion transcription factor PML/RARα resulting from the causative chromosomal rearrangement (15;17) has been shown to interact with transcription factor PU.1 to repress the expression of all βi subunits [ 164 ].…”