Unravel the molecular mechanism of XBP1 in regulating the biology of cancer cells

Shi, Weimei; Chen, Zhixi; Li, Linfu; Lü, Hai; Zhang, Rui; Cheng, Qilai; Xu, Daohua; Wu, Longhuo

doi:10.7150/jca.29421

Cited by 49 publications

(45 citation statements)

References 115 publications

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“…The genes controlled by the spliced XBP1 variant encode a variety of proteins involved in the adaptive modulation of protein folding, secretion, and translocation to the ER, as well as in the ERAD and lipid synthesis [61][62][63]. However, XBP1 upregulates also the expression of several oncogenic factors, thereby promoting carcinogenesis, neoplastic cell survival, drug-resistance, and tumor progression [64]. Furthermore, IRE1α RNase activity is involved in controlling the RNA degradation pathway referred to as regulated IRE1α-dependent decay (RIDD) [65].…”

Section: Ire1αmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

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Section: Ire1αmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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“…The PERK-EIF2α axis enhances ATF4. Both XBP1s and ATF4 function as transcription factors that regulate a wide range of genes, which plays a crucial role in cell adaptation to stress conditions 29,30 .…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells

et al. 2020

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To address unmet clinical need for uveal melanomas, we assessed the effects of BH3-mimetic molecules, the ABT family, known to exert pro-apoptotic activities in cancer cells. Our results uncovered that ABT-263 (Navitoclax), a potent and orally bioavailable BCL-2 family inhibitor, induced antiproliferative effects in metastatic human uveal melanoma cells through cell cycle arrest at the G0/G1 phase, loss of mitochondrial membrane potential, and subsequently apoptotic cell death monitored by caspase activation and poly-ADP ribose polymerase cleavage. ABT-263-mediated reduction in tumor growth was also observed in vivo. We observed in some cells that ABT-263 treatment mounted a pro-survival response through activation of the ER stress signaling pathway. Blocking the PERK signaling pathway increased the pro-apoptotic ABT-263 effect. We thus uncovered a resistance mechanism in uveal melanoma cells mediated by activation of endoplasmic reticulum stress pathway. Therefore, our study identifies ABT-263 as a valid therapeutic option for patients suffering from uveal melanoma.

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“…There is increasing evidence demonstrating that XBP1 may be a potential oncogenic gene (11,35). Through multiply molecular mechanisms, XBP1 plays a role in regulating the biology of cancer cells, such as proliferation, invasion, migration, apoptosis, and drug resistance (11,15). XBP1 presents overexpressed in various certain human cancer tissues and plays an oncogenic role in carcinogenesis and progression.…”

Section: Discussionmentioning

confidence: 99%

“…Commonly, XBP1 exists in two isoforms: un-spliced XBP1 and spliced XBP1 (XBP1s). The splicing of un-spliced XBP1 results in the generation of XBP1s, which is catalyzed by inositol-requiring enzyme 1α (IRE1α) (11). XBP1 is involved in maintaining endoplasmic reticulum (ER) homeostasis.…”

Section: Introductionmentioning

confidence: 99%

“…XBP1 is related to some human diseases, including cancer. For example, XBP1 is involved in the development and progression of cancer by modulating cancer cell proliferation, apoptosis, invasion, metastasis, and drug resistance (11,14,15). Previous studies reported that XBP1 was overexpressed in various human cancer types, such as breast cancer, oral cancer, lung cancer, colorectal cancer, and hepatocellular cancer (14,(16)(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

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Prognostic and Clinicopathological Significance of X-Box-Binding Protein 1 and N-Acetyltransferase 1 in Gallbladder Cancer

Liu

Miao

et al. 2020

Front. Oncol.

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Background: X-box-binding protein 1 (XBP1) and N-acetyltransferase 1 (NAT1) are involved in oncogenesis and progression of many human cancer types. However, the roles of XBP1 and NAT1 in gallbladder cancer (GBC) are never reported. Methods: We examined XBP1 and NAT1 expression in GBC and matched adjacent non-tumor tissues via Western blotting. Then, we assayed XBP1 and NAT1 expression in 215 GBCs, including 69 squamous cell/adenosquamous carcinomas (SC/ASCs) and 146 adenocarcinomas (ACs) with immunohistochemistry. Their prognostic and clinicopathological significance was further evaluated using the χ 2 test or Fisher's exact test, Kaplan-Meier univariate survival analysis, and log-rank tests. Results: XBP1 expression was upregulated, and NAT1 expression was downregulated in GBC. Immunohistochemical results showed that XBP1 expression was negatively associated with NAT1 expression in GBC, including SC/ASC and AC. The rate of patients with an age of more than 45 years, positivity of lymph node metastasis, and invasion were significantly higher in SC/ASC than those in AC (all P < 0.05). The percentage of XBP1-positive and NAT1-negative expression was significantly higher in the cases with poor differentiation, advanced tumor, nodes, and metastases (TNM) stage, lymph node metastasis, invasion, and only receiving biopsy in GBC, SC/ASC, and AC (all P < 0.05). XBP1-positive and NAT1-negative expression was positively related to larger tumor size (>3 cm) in GBC and AC. There was a negative association between XBP1 and NAT1 expression in GBC, SC/ASC, and AC (all P < 0.05). Positive XBP1 and negative NAT1 expression was closely associated with decreased overall survival in GBC, SC/ASC, and AC patients (all P < 0.05). The multivariate Cox regression analysis showed that positive Liu et al. XBP1 and NAT1 in GBC XBP1 or negative NAT1 expression was an independent factor for poor prognosis in gallbladder SC/ASC and AC patients. Conclusions: This study indicates that positive XBP1 and negative NAT1 expression are closely associated with the clinicopathological and biological behaviors and poor prognosis in GBC.

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Unravel the molecular mechanism of XBP1 in regulating the biology of cancer cells

Cited by 49 publications

References 115 publications

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells

Prognostic and Clinicopathological Significance of X-Box-Binding Protein 1 and N-Acetyltransferase 1 in Gallbladder Cancer

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