Endoplasmic reticulum chaperone GRP78/BiP is critical for mutant Kras-driven lung tumorigenesis

Abstract

Lung cancer is the leading cause of cancer mortality worldwide and KRAS is the most commonly mutated gene in lung adenocarcinoma (LUAD). The 78-kDa glucose-regulated protein GRP78/BiP is a key endoplasmic reticulum (ER) chaperone protein and a major pro-survival effector of the unfolded protein response (UPR). Analysis of the Cancer Genome Altas (TCGA) database and immunostain of patient tissues revealed that compared to normal lung, GRP78 expression is generally elevated in human lung cancers, including tumors bearing the KRAS G12D mutation. To test the requirement of GRP78 in human lung oncogenesis, we generated mouse models containing floxed Grp78 and Kras Lox-Stop-Lox G12D (Kras LSL-G12D ) alleles. Simultaneous activation of the Kras G12D allele and knockout of the Grp78 alleles were achieved in the whole lung or selectively in lung alveolar epithelial type 2 cells known to be precursors for adenomas which progress to LUAD. Here we report that GRP78 haploinsufficiency is sufficient to suppress Kras G12D -mediated lung tumor progression and prolong survival. Furthermore, GRP78 knockdown in human lung cancer cell line A427 (Kras G12D/+ ) leads to activation of UPR and *

Novel mutation in EFEMP1 identified from two Chinese POAG families differentially activated endoplasmic reticulum stress markers and induced glaucoma in mouse

“…Those differential intracellular protein aggregations might affect the activation levels of downstream signals. This was further supported by the expression of ER stress markers, such as ER chaperones glucose-regulated protein 78 (GRP78), GRP94, and complement C3, [19][20][21] which were significantly induced by M59, R140, or R345 variants, but not by WT. This difference was also observed in other ER stress and UPR marker such as CALR 22 and ATF4.…”

“…18,19 We then argued whether ER stress or unfolded protein response (UPR) can be activated by those EFEMP1 mutants. We assessed the RNA expression of selected markers of ER stress/UPR [18][19][20][21][22][23] using qPCR assay. As expected, compared to WT EFEMP1, the levels of RNA expressions for Glucose Related Protein (GRP) 78, GRP94, Calreticulin (CALR), and activating transcription factor 4 (ATF4), but not for C/EBP homologous protein (CHOP), were significantly increased in M59 (Figure 3E-I).…”

The ER chaperone, BIP protects Microglial cells from ER stress-mediated Apoptosis in Hyperglycemia

“…The in-vivo streptozotocin-induced diabetes mouse model also revealed that BIP repression induced the ER stress through the activation of CHOP and hyperphosphorylation of eIF2α. Previous studies have also shown that the knockdown of BIP increased the phosphorylation of eIF2α, and increased CHOP expression in both in-vitro and in-vivo models [29]. Inhibition or suppression of BIP could induce the compensatory mechanism by the upregulation of ER chaperones.…”

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

“…A study based on cell experiments found that the simultaneous inhibition of activated Cdc42-associated kinase (ACK1) and AKT inhibited the growth and migration of KRAS-mutant NSCLC cells, providing the premise for the clinical translation of ACK1 and AKT inhibitors either as monotherapy or with rational combination [ 128 ]. GRP78 haploinsufficiency is reported to inhibit KRAS G12D-mediated tumor progression and prolong survival, and it is a potential therapeutic target for KRAS-mutant lung cancer [ 129 ]. It has also been found that regenerating family member (REG4) is highly expressed in KRAS-mutant lung adenocarcinoma, and that silencing REG4 can inhibit cancer cell proliferation and genesis, making it a potential therapeutic target [ 130 ].…”