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Common cytotoxic chemotherapeutics induce epithelial-mesenchymal transition (EMT) downstream of ER stress.

ABSTRACT: Endoplasmic reticulum (ER) in eukaryotes is a main organelle involved in a wide variety of functions including calcium storage, lipid biosynthesis, protein folding and protein transport. Disruption of ER homeostasis leads to ER stress and activation of the unfolded protein response (UPR). We and others have previously found that ER stress induces EMT in different cellular systems. Induction of ER stress with chemical modulators of ER homeostasis was sufficient to activate an EMT-like state in all cellular systems tested. Here, we provide evidence for the first time demonstrating that ER stress induces EMT that is neither cancer cell specific nor cell-type specific. In addition, we observed that chemotherapeutic drugs commonly used to treat patients also activate ER stress that is concomitant with activation of an EMT-like state. Interestingly, we find that following removal of ER stress, partial EMT characteristics still persist indicating that ER stress induced EMT is a long-term effect. Induction of mesenchymal characteristics, following chemotherapeutics treatment may be involved in providing cancer stemness and invasiveness in the cellular system. Interestingly, we find that mice treated with cisplatin have elevated level of ER stress and EMT markers in multiple tissues including lung, liver and kidneys. Furthermore, increased ER stress, as demonstrated by increased Bip, Chop, PDI, Ero1? and IRE1, and EMT, as demonstrated by increased Vimentin and Snail, is a hallmark of primary lung adenocarcinoma samples from patients. These observations have potential clinical relevance because overexpression of ER stress and EMT markers might contribute to chemoresistance and poor survival of lung adenocarcinoma patients.

SUBMITTER: Shah PP

PROVIDER: S-EPMC5410250 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Common cytotoxic chemotherapeutics induce epithelial-mesenchymal transition (EMT) downstream of ER stress.

Shah Parag P PP Dupre Tess V TV Siskind Leah J LJ Beverly Levi J LJ

Oncotarget 20170401 14

Endoplasmic reticulum (ER) in eukaryotes is a main organelle involved in a wide variety of functions including calcium storage, lipid biosynthesis, protein folding and protein transport. Disruption of ER homeostasis leads to ER stress and activation of the unfolded protein response (UPR). We and others have previously found that ER stress induces EMT in different cellular systems. Induction of ER stress with chemical modulators of ER homeostasis was sufficient to activate an EMT-like state in al ...[more]

PMID: 28186986

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Project description:During progression of melanoma, malignant melanocytes can be reprogrammed into mesenchymal-like cells through a process similar to epithelial-mesenchymal transition (EMT), which is associated with downregulation of the junctional protein E-cadherin and acquisition of a migratory phenotype. Recent evidence supports a role for SLUG, a transcriptional repressor of E-cadherin, as a melanocyte lineage transcription factor that predisposes to melanoma metastasis. However, the signals responsible for SLUG expression in melanoma are unclear and its role in the invasive phenotype is not fully elucidated. Here, we report that SLUG expression and activation is driven by SPARC (also known as osteonectin), a secreted extracellular matrix-associated factor that promotes EMT-like changes. Ectopic expression or knockdown of SPARC resulted in increased or reduced expression of SLUG, respectively. SLUG increase occurred concomitantly with SPARC-mediated downregulation of E-cadherin and P-cadherin, and induction of mesenchymal traits in human melanocytes and melanoma cells. Pharmacological blockade of PI3 kinase/AKT signaling impeded SPARC-induced SLUG levels and cell migration, whereas adenoviral introduction of constitutively active AKT allowed rescue of SLUG and migratory capabilities of SPARC knockdown cells. We also observed that pharmacological inhibition of oncogenic BRAF(V600E) using PLX4720 did not influence SLUG expression in melanoma cells harboring BRAF(V600E). Furthermore, SLUG is a bona fide transcriptional repressor of E-cadherin as well as a regulator of P-cadherin in melanoma cells and its knockdown attenuated invasive behavior and blocked SPARC-enhanced cell migration. Notably, inhibition of cell migration in SPARC-depleted cells was rescued by expression of a SLUG transgene. In freshly isolated metastatic melanoma cells, a positive association between SPARC and SLUG mRNA levels was also found. These findings reveal that autocrine SPARC maintains heightened SLUG expression in melanoma cells and indicate that SPARC may promote EMT-associated tumor invasion by supporting AKT-dependent upregulation of SLUG.

Dataset Information

Common cytotoxic chemotherapeutics induce epithelial-mesenchymal transition (EMT) downstream of ER stress.

Publications

Common cytotoxic chemotherapeutics induce epithelial-mesenchymal transition (EMT) downstream of ER stress.

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