KDELR2 knockdown synergizes with temozolomide to induce glioma cell apoptosis through the CHOP and JNK/p38 pathways

Abstract

Background: The C-terminal tetrapeptide Lys-Asp-Glu-Leu receptors (KDELRs) are transmembrane proteins that regulate ER stress (ERS) response, growth, differentiation, and immune responses. There is an association between KDELR2and promotion of glioblastoma tumorigenesis. The aim of the present study was to explore the functional mechanism of KDELR2 in glioma and during response to chemotherapy to temozolomide (TMZ).Methods: The expression of KDELR2 in glioma tissues and cells was evaluated by immunohistochemistry, western blot and RT-qPCR assay. Then role of KDELR2 was demonstrated by CCK8, colony formation, flow cytometry and Hochest 33258 assays. The expression of genes (ATF4, ATF6, PERK, eIF2-α, GRP78 and CHOP) in U373 cells was evaluated by RT-qPCR. The protein expression of genes (cleaved caspase 3, caspase 3, cleaved PARP, PARP, Bax, Bcl-2, JNK, p-JNK, p38, p-p38, ATF4, ATF6, XBP-1s, PERK, p-PERK, GRP78 and CHOP) was measured by western blot assay.Results: The expression of KDELR2 was upregulated in high-grade gliomas tissues. KDELR2 knockdown suppressed cell proliferation but increased cell apoptosis. Further, Knockdown of KDELR2 also activated the ER stress (ERS)-dependent CHOP pathway, and resulted in increased levels of phosphorylated c-Jun N-terminal kinase (JNK) and p38. Moreover, the combination of KDELR2 knockdown and TMZ application showed a synergistic cytotoxic effect in U373 cells through the ERS-dependent CHOP and JNK/p38 pathways.Conclusions: KDELR2 knockdown induces apoptosis and sensitizes glioma cells to TMZ, which is mediated by the ERS-dependent CHOP and JNK/p38 pathways.

Glutathione S-Transferases S1, Z1 and A1 Serve as Prognostic Factors in Glioblastoma and Promote Drug Resistance through Antioxidant Pathways

“…The JNK pathway has been found to interact with multiple GST enzymes, including GSTP1 [ 37 , 38 , 39 ], and these interactions have been shown to promote apoptosis in glioma [ 40 , 41 , 42 ]. We thus hypothesized that the enhancing of drug resistance in GBM by HPGDS may be partially dependent on its inhibition of JNK pathway activation.…”

KDEL Receptors: Pathophysiological Functions, Therapeutic Options, and Biotechnological Opportunities

“…Finally, several studies described the involvement of KDELRs in the development and progression of cancer [ 64 , 65 , 66 , 72 , 73 , 74 , 75 , 76 ], but this aspect will not be fully addressed here because it deserves extensive and dedicated discussion. In short, interfering with KDELR1, KDELR2, and KDELR3 was found to reduce leukemic cell proliferation and hinder glioblastoma growth and invasiveness of metastatic melanoma, respectively [ 64 , 65 , 66 , 72 , 73 , 74 ]. These findings repurpose a specialization among the three KDELR isoforms and suggest that as yet unknown signaling pathways could be exploited by KDELRs.…”

“…KDELRs are multifaceted proteins, and although further studies will be required to fully characterize their functions, they can be considered potential targets for the development of novel therapeutic strategies for a variety of diseases. Targeting KDELRs may have beneficial effects in pathologies involving the disruption of proteostasis [ 40 , 54 , 55 ], in cancer progression [ 64 , 65 , 66 , 73 , 74 , 75 , 76 ], as well as in infectious and intoxication diseases by inhibiting the spreading of viral particles and the entry of toxins [ 78 , 81 , 83 ]. Unfortunately, no pharmacological approach has yet been developed to specifically target KDELRs, with the exception of some drugs, which, by modulating ER-stress and UPR responses, could indirectly involve KDELRs [ 92 , 93 , 94 ].…”