bims-istrec 2022-08-07 papers

Issue of 2022‒08‒07
three papers selected by
the Vincenzo Ciminale lab
Istituto Oncologico Veneto

Toxicol Appl Pharmacol. 2022 Jul 29. pii: S0041-008X(22)00323-4. [Epub ahead of print] 116178

Vitamin D3 and Salinomycin synergy in MCF-7 cells cause cell death via endoplasmic reticulum stress in monolayer and 3D cell culture.

Lilian Areal Marques, Simone Cristine Semprebon, Bruna Isabela Biazi, Ingrid Felicidade, Thalita Alves Zanetti, Adrivanio Baranoski, Virgínia Márcia Concato, Wander Rogério Pavanelli, Mário Sérgio Mantovani.

1α, 25, dihydroxyvitamin D3 (1,25D), the active form of vitamin D3, has antitumor properties in several cancer cell lines in vitro. Salinomycin (Sal) has anticancer activity against cancer cell lines. This study aims to examine the cytotoxic and antiproliferative effect of Sal associated with 1,25D on MCF-7 breast carcinoma cell line cultured in monolayer (2D) and three-dimensional models (mammospheres). We also aim to evaluate the molecular mechanism of Sal and 1,25D-mediated effects. We report that Sal and 1,25D act synergistically in MCF-7 mammospheres and monolayer causing G1 cell cycle arrest, reduction of mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) overproduction with a long-lasting cytotoxic response represented by clonogenic and mammosphere assay. We observed the induction of cell death by apoptosis with upregulation in mRNA levels of apoptosis-related genes (CASP7, CASP9, and BBC3). Extensive cytoplasmic vacuolization, a morphological characteristic found in paraptosis, was also seen and could be triggered by endoplasmic reticulum stress (ER) as we found transcriptional upregulation of genes related to ER stress (ATF6, GADD153, GADD45G, EIF2AK3, and HSPA5). Overall, Sal and 1,25D act synergistically, inhibiting cell proliferation by activating simultaneously multiple death pathways and may be a novel and promising luminal A breast cancer therapy strategy.

Keywords: 1,25 Dihydroxyvitamin D(3); Autophagy; Breast cancer; Mammosphere; Paraptosis

DOI: https://doi.org/10.1016/j.taap.2022.116178

J Cell Sci. 2022 Aug 01. pii: jcs.258396. [Epub ahead of print]

TGFBR3 supports anoikis through suppressing ATF4 signaling.

Yu-Jhen Hsu, Yih-Jia Yin, Kai-Feng Tsai, Cian-Chun Jian, Zi-Wen Liang, Chien-Yu Hsu, Chun-Chao Wang.

Epithelial morphogenesis and oncogenic transformation can cause loss of cell adhesion, and detached cells are eliminated by anoikis. Here, we reveal that transforming growth factor beta receptor 3 (TGFBR3) acts as an anoikis mediator through the coordination of activating transcription factor 4 (ATF4). In breast cancer, TGFBR3 is progressively lost, but elevated TGFBR3 is associated with a histologic subtype characterized by cellular adhesion defects. Dissecting the impact of extracellular matrix (ECM) deprivation, we demonstrate that ECM loss promotes TGFBR3 expression, which in turn differentiates cell aggregates to a prosurvival phenotype and drives the intrinsic apoptotic pathway. We demonstrate that inhibition of TGFBR3 impairs epithelial anoikis by activating ATF4 signaling. These preclinical findings provide a rationale for therapeutic inhibition of ATF4 in the subgroup of breast cancer patients with low TGFBR3 expression.

Keywords: Activating transcription factor 4; Anoikis; Breast cancer; Integrated stress response; Transforming growth factor beta

DOI: https://doi.org/10.1242/jcs.258396

Front Genet. 2022 ;13 938787

Yongshi Liu, Xiaohua Liang, Hongpei Zhang, Jiajia Dong, Yan Zhang, Juan Wang, Chunmei Li, Xiangbing Xin, Yan Li.

Objective: This study aimed to evaluate the associations between endoplasmic reticulum (ER) stress-related genes EIF2AK3/PERK, HSPA5/GRP78, and DDIT3/CHOP polymorphisms and the risk of lung cancer. Methods: Six single-nucleotide polymorphisms (SNPs) of EIF2AK3, HSPA5, and DDIT3 were genotyped in 620 cases and 620 controls using a MassARRAY platform. Results: The minor allele A of rs6750998 was a protective allele against the risk of lung cancer (p < 0.001), while the minor alleles of rs867529, rs391957, and rs697221 were all risk alleles that may lead to multiplied risk of the disease (rp rs867529 = 0.002; p rs391957 = 0.015; p rs697221 < 0.001). Moreover, the rs6750998-TA/AA genotypes were protective genotypes against the risk of lung cancer (p = 0.005); however, the rs867529-GC/CC, rs391957-CC, and rs697221-GA/AA genotypes were associated with elevated lung cancer risk (p rs867529 = 0.003, p rs391957 = 0.028, and p rs697221 = 0.0001). In addition, EIF2AK3-rs6750998 was associated with a decreased risk of lung cancer under dominant, recessive, and log-additive models (p < 0.05). By contrast, the EIF2AK3-rs867529 was correlated with an increased risk of the disease under dominant and log-additive models (p = 0.001). Moreover, HSPA5-rs391957 was related to an elevated risk of the disease under recessive and log-additive models (p < 0.02). DDIT3-rs697221 was identified to have a significant association with the risk of lung cancer under all three genetic models (p < 0.01). Conclusion: Our results provide new insights on the role of the ER stress-related genes EIF2AK3, HSPA5, and DDIT3 polymorphisms for lung cancer risk.

Keywords: case–control study; endoplasmic reticulum stress; gene polymorphisms; lung cancer; single-nucleotide polymorphisms

DOI: https://doi.org/10.3389/fgene.2022.938787