Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib

Abstract

Background: Inositol-requiring enzyme 1α (IRE1α), along with protein kinase R-like endoplasmic reticulum kinase (PERK), is a principal regulator of the unfolded protein response (UPR). Recently, the ‘mono’-specific IRE1α inhibitor, kinase-inhibiting RNase attenuator 6 (KIRA6), demonstrated a promising effect against multiple myeloma (MM). Side-stepping the clinical translation, a detailed UPR phenotype in patients with MM and the mechanisms of how KIRA8 works in MM remains unclear. Methods: We characterized UPR phenotypes in the bone marrow of patients with newly diagnosed MM. Then, in human MM cells we analyzed the possible anti-tumor mechanisms of KIRA8 and a Food and Drug Administration (FDA)-approved drug, nilotinib, which we recently identified as having a strong inhibitory effect against IRE1α activity. Finally, we performed an RNA-sequence analysis to detect key IRE1α-related molecules against MM. Results: We illustrated the dominant induction of adaptive UPR markers under IRE1α over the PERK pathway in patients with MM. In human MM cells, KIRA8 decreased cell viability and induced apoptosis, along with the induction of C/EBP homologous protein (CHOP); its combination with bortezomib exhibited more anti-myeloma effects than KIRA8 alone. Nilotinib exerted a similar effect compared with KIRA8. RNA-sequencing identified Polo-like kinase 2 (PLK2) as a KIRA8-suppressed gene. Specifically, the IRE1α overexpression induced PLK2 expression, which was decreased by KIRA8. KIRA8 and PLK2 inhibition exerted anti-myeloma effects with apoptosis induction and the regulation of cell proliferation. Finally, PLK2 was pathologically confirmed to be highly expressed in patients with MM. Conclusion: Dominant activation of adaptive IRE1α was established in patients with MM. Both KIRA8 and nilotinib exhibited anti-myeloma effects, which were enhanced by bortezomib. Adaptive IRE1α signaling and PLK2 could be potential therapeutic targets and biomarkers in MM.

IRE1a-Induced FilaminA Phosphorylation Enhances Migration of Mesenchymal Stem Cells Derived from Multiple Myeloma Patients

“…Moreover, the disruption of the IRE1a-XBP1s axis was shown to reduce the viability and drug resistance of MM cells in different contexts [17][18][19]. For example, anti-IRE1a drugs, such as nilotinib and KIRA8, showed beneficial effects against MM in synergy with bortezomib and lenalidomide [20]. On the other hand, it is known that IREa-XBP1s can regulate protumor environment acting also in non-tumor cells such as osteoclasts and BMMSCs [21,22].…”

“…These events lead to the resolution of ER stress, reached with a reduction in mRNA translation and protein folding, as well as to cell survival. It is not surprising that this pathway, in particular the IRE1a-XBP1s axis, is activated in MM cells to avoid apoptosis caused by ER stress, due to abnormal IgG production, and that it is involved in MM chemoresistance [17][18][19][20]. Previous publications showed that the inhibition or disruption of the IRE1a-XBP1s axis in MM cells can reduce tumor progression [17][18][19] and can synergize with MM-specific drugs such as bortezomib and lenalidomide [17,20].…”

“…It is not surprising that this pathway, in particular the IRE1a-XBP1s axis, is activated in MM cells to avoid apoptosis caused by ER stress, due to abnormal IgG production, and that it is involved in MM chemoresistance [17][18][19][20]. Previous publications showed that the inhibition or disruption of the IRE1a-XBP1s axis in MM cells can reduce tumor progression [17][18][19] and can synergize with MM-specific drugs such as bortezomib and lenalidomide [17,20]. Interestingly, the activation of the IRE1a-XBP1s pathway in non-tumor cells of the MM bone marrow microenvironment can contribute to tumor progression.…”

Polo-Like Kinase 2: From Principle to Practice

“…For example, interference with PLK2 might lead to the loss of interaction with miR-101-3p target gene SKP1, and the accumulation of cotransfected overexpressed α-Syn protein due to decreased ubiquitination degradation, leading to ER stress of neurons, suggesting that PLK2 could prevent ER stress ( 28 ). PLK2 is hyper-expressed in multiple myeloma (MM) patients; PLK2 further inhibits C/EBP homologous protein (CHOP) and enhances inositol-requiring enzyme 1α (IRE1α) by inhibiting KIRA8 (kinase-inhibiting RNase attenuator 8), which in turn affects ER stress and facilitates cell survival; Meanwhile, KIRA8/IRE1α could reversely regulate PLK2 expression; KIRA8 and PLK2 inhibitors exert anti-MM effects by inducing apoptosis and regulating cell proliferation ( 81 ). In ER stress induced by Brefeldin A (BFA), increased binding of CHOP to the PLK2 promoter C/EBPα response element results in downregulation of PLK2 expression; Overexpression of exogenous PLK2 could inhibit cell apoptosis and promote cell proliferation ( 82 ).…”

“…Like its compatriots, the role of PLK2 in tumor has attracted considerable attention. Although it is reported that PLK2 is highly expressed in MM and facilitates tumor cell vitality by inhibiting KIRA8 induced CHOP mediated apoptosis ( 81 ), more studies have showed PLK2 acts as a tumor suppressor in hematological neoplasma. In B-cell lymphoma ( 26 ), acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) ( 90 ), remarkable reduction of PLK2 expression might be related to abnormal methylation.…”