Gemcitabine Induces the VMP1 -Mediated Autophagy Pathway to Promote Apoptotic Death in Human Pancreatic Cancer Cells

Pardo, Romina Paola; Ré, Andrea Lo; Archange, Cendrine; Ropolo, Alejandro; Papademetrio, Daniela L.; Gonzalez, Claudio; Álvarez, Élida; Iovanna, Juan; Vaccaro, María I.

doi:10.1159/000264680

Cited by 87 publications

(84 citation statements)

References 26 publications

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“…On the other hand, gemcitabine, the standard chemotherapy for PC, has been shown to induce autophagy and potentiate apoptotic cell death in PC, while autophagy blockage attenuated apoptotic cell death. This suggests that induction of autophagy promotes gemcitabineinduced apoptotic cell death (30). SFN-induced cell death and autophagy signaling are independent of each other.…”

Section: Discussionmentioning

confidence: 93%

Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer

Naumann

Fortunato

Zentgraf³

et al. 2011

Int J Oncol

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Abstract. the broccoli isothiocyanate, sulforaphane (Sfn), was recently identified as being capable of eliminating highly therapy-resistant pancreatic carcinoma (PC) cells without inducing toxic side effects. While SFN has been shown to stimulate autophagy or 'self-eating', it is unclear whether this catabolic process is a pro-or anti-tumorigenic response. To investigate the role of autophagy in SFN-induced cell death, established PC cell lines were treated with SFN, and the induction of autophagy was evaluated by detecting the abundance of autophagic vesicles by electron microscopy, the increase in converted LC3-II by Western blot analysis and the autophagosome puncta of GFP-LC3 by immunofluorescence. SFN-induced autophagy was suppressed by the autophagy inhibitor chloroquine, while the autophagy inducer rapamycin did not further enhance autophagy in PC cells. Importantly, neither modulator altered SFN cytotoxicity, suggesting that SFN-induced autophagy and cell death act independently of each other. In contrast, the antioxidant N-acetyl-cysteine sustained cell viability and prevented autophagy induction after SFN exposure, indicating that both signaling pathways depend on reactive oxygen species (ROS). Our studies provide a valuable new mechanistic insight into the SFN-induced elimination of PC cells and suggest that an SFN-enriched diet potentially enhances ROS-releasing chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 93%

Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer

Naumann

Fortunato

Zentgraf³

et al. 2011

Int J Oncol

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show abstract

“…Autophagy, or autophagocytosis, is a reversible process in which intracellular components are sequestered and degraded in double membrane autophagosomes (28). This strategy may serve to temporarily protect cells from cytotoxic stimuli, but can progress to apoptosis after prolonged cellular stress (29). The number of autophagosomes correlates to the amount of lipidated LC3B-II protein found in the cell and is generally considered to be a hallmark of autophagy (30).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Fuhler

Brooks

Toms

et al. 2011

Mol Med

114

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Many tumors present with increased activation of the phosphatidylinositol 3-kinase (PI3K)-PtdIns(3,4,5)P 3 -protein kinase B (PKB/Akt) signaling pathway. It has long been thought that the lipid phosphatases SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 act as tumor suppressors by counteracting with the survival signal induced by this pathway through hydrolysis or PtdIns(3,4,5)P 3 to PtdIns(3,4)P 2 . However, a growing body of evidence suggests that PtdInd(3,4)P 2 is capable of, and essential for, Akt activation, thus suggesting a potential role for SHIP1/2 enzymes as proto-oncogenes. We recently described a novel SHIP1-selective chemical inhibitor (3α-aminocholestane [3AC]) that is capable of killing malignant hematologic cells. In this study, we further investigate the biochemical consequences of 3AC treatment in multiple myeloma (MM) and demonstrate that SHIP1 inhibition arrests MM cell lines in either G0/G1 or G2/M stages of the cell cycle, leading to caspase activation and apoptosis. In addition, we show that in vivo growth of MM cells is blocked by treatment of mice with the SHIP1 inhibitor 3AC. Furthermore, we identify three novel pan-SHIP1/2 inhibitors that efficiently kill MM cells through G2/M arrest, caspase activation and apoptosis induction. Interestingly, in SHIP2-expressing breast cancer cells that lack SHIP1 expression, pan-SHIP1/2 inhibition also reduces viable cell numbers, which can be rescued by addition of exogenous PtdIns(3,4)P 2 . In conclusion, this study shows that inhibition of SHIP1 and SHIP2 may have broad clinical application in the treatment of multiple tumor types.

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“…We suggest that inhibition of AURKA will sensitize preferentially intrapancreatic tumor cells located near hypovascularized regions, which should correspond to the most resistant cells because they have been selected after exposure to an adverse microenvironment. Autophagy seems to be required for pancreatic cancer development (48), although in other conditions, it can also oppose cancer progression (49,50). Therefore, autophagic process in cancer has different effects on cell fate depending on the cellular type and the nature of the induction.…”

Section: Discussionmentioning

confidence: 99%

Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death

Hamidi

Cano

Grasso

et al. 2012

Clinical Cancer Research

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Purpose: The limited supply of oxygen and nutrients is thought to result in rigorous selection of cells that will eventually form the tumor.Experimental Design: Nupr1 expression pattern was analyzed in human tissue microarray (TMA) and correlated with survival time of the patient. Microarray analysis was conducted on MiaPaCa2 cells subjected to metabolic stress in Nupr1-silenced conditions. DNA repair and cell cycle-associated gene expression was confirmed by real-time quantitative PCR (qRT-PCR). Nupr1 and AURKA protective role were analyzed using RNA interference (RNAi) silencing or overexpression. DNA damage and autophagy were analyzed by Western blot analysis and immunofluorescence.Results: We showed that both Nupr1 and HIF1a are coexpressed in human pancreatic ductal adenocarcinoma (PDAC) samples and negatively correlate with survival time. PDAC-derived cells submitted to hypoxia and/or glucose starvation induce DNA damage-dependent cell death concomitantly to the overexpression of stress protein Nupr1. Affymetrix-based transcriptoma analysis reveals that Nupr1 knockdown enhances DNA damage and alters the expression of several genes involved in DNA repair and cell-cycle progression. Expression of some of these genes is common to hypoxia and glucose starvation, such as Aurka gene, suggesting that Nupr1 overexpression counteracts the transcriptional changes occurring under metabolic stress. The molecular mechanism by which hypoxia and glucose starvation induce cell death involves autophagy-associated, but not caspase-dependent, cell death. Finally, we have found that AURKA expression is partially regulated by Nupr1 and plays a major role in this response.Conclusions: Our data reveal that Nupr1 is involved in a defense mechanism that promotes pancreatic cancer cell survival when exposed to metabolic stress.

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Gemcitabine Induces the VMP1 -Mediated Autophagy Pathway to Promote Apoptotic Death in Human Pancreatic Cancer Cells

Cited by 87 publications

References 26 publications

Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer

Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death

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