PDK2-mediated alternative splicing switches Bnip3 from cell death to cell survival

Hao, Gang; Dhingra, Rimpy; Lin, Junjun; Yan, Hai; Aviv, Yaron; Margulets, Victoria; Hamedani, Mohammad K.; Thanasupawat, Thatchawan; Leygue, Etienne; Klonisch, Thomas; Davie, James R.; Kirshenbaum, Lorrie A.

doi:10.1083/jcb.201504047

Cited by 32 publications

(25 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PDK2 belongs to the pyruvate dehydrogenase kinase family. It can downregulate the activity of the mitochondrial pyruvate dehydrogenase complex . By reducing the conversion of pyruvate to acetyl‐CoA, PDK2 switches carbon flow from the tricarboxylic acid cycle and de novo lipogenesis to lactate production, thus facilitating Warburg effect .…”

Section: Discussionmentioning

confidence: 99%

“…It can downregulate the activity of the mitochondrial pyruvate dehydrogenase complex . By reducing the conversion of pyruvate to acetyl‐CoA, PDK2 switches carbon flow from the tricarboxylic acid cycle and de novo lipogenesis to lactate production, thus facilitating Warburg effect . Dysregulation of PDK2 is reported in multiple cancers, and linked to proliferation, metastasis, and chemoresistance of cancer cells .…”

Section: Discussionmentioning

confidence: 99%

“…32,33 By reducing the conversion of pyruvate to acetyl-CoA, PDK2 switches carbon flow from the tricarboxylic acid cycle and de novo lipogenesis to lactate production, thus facilitating Warburg effect. 33 Dysregulation of PDK2 is reported in multiple cancers, and linked to proliferation, metastasis, and chemoresistance of cancer cells. [34][35][36][37] Specifically, in HCC, PDK2 is identified as target of miR-214, and involved in disease progression.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Long noncoding RNA DUXAP8 contributes to the progression of hepatocellular carcinoma via regulating miR‐422a/PDK2 axis

et al. 2020

View full text Add to dashboard Cite

Background Hepatocellular carcinoma (HCC) is one of the most deadly cancer worldwide. Multiple long noncoding RNAs (lncRNAs) are recently identified as crucial oncogenic factors or tumor suppressors. In this study, we explored the functon and mechanism of lncRNA double homeobox A pseudogene 8 (DUXAP8) in the progression of HCC. Methods Expression levels of DUXAP8 in HCC tissue samples were measured using qRT‐PCR. The association between pathological indexes and the expression of DUXAP8 was also analyzed. Human HCC cell lines SMMC‐7721 and QSG‐7701 were used in in vitro studies. CCK‐8 assay was used to assess the effect of DUXAP8 on HCC cell line proliferation. Scratch healing assay and Transwell assay were conducted to detect the effect of DUXAP8 on migration and invasion. Furthermore, dual‐luciferase reporter assay was used to confirm targeting relationship between miR‐422a and DUXAP8. Additionally, Western blot was used to detect the regulatory function of DUXAP8 on pyruvate dehydrogenase kinase 2 (PDK2). Results DUXAP8 expression HCC clinical samples was significantly increased and this was correlated with unfavorable pathological indexes. High expression of DUXAP8 was associated with shorter overall survival time of patients. Its overexpression remarkably facilitated the proliferation, metastasis, and epithelial‐mesenchymal transition of HCC cells. Accordingly, knockdown of it suppressed the malignant phenotypes of HCC cells. Overexpression of DUXAP8 significantly reduced the expression of miR‐422a by sponging it, but enhanced the expression of PDK2. Conclusions DUXAP8 was a sponge of tumor suppressor miR‐422a in HCC, enhanced the expression of PDK2 indirectly, and functioned as an oncogenic lncRNA.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Long noncoding RNA DUXAP8 contributes to the progression of hepatocellular carcinoma via regulating miR‐422a/PDK2 axis

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Specially, SEV, which exhibited the most heightened release under hypoxia, shifted toward a smaller size distribution (~19% and 48% decrease on an average for MiaPaCa and AsPC1 cells, respectively) under extreme hypoxia (0.1% O 2 ). 43,44 A recent study in pancreatic cancer, however, reported that EV derived from hypoxic tumor cells contained miR-301a, which was involved in M2 macrophage polarization. Although underlying reason(s) for this altered size distribution are not clear, one could argue that since under hypoxia metabolites become limiting, smaller size shift could be a strategy of cells to restrict their loss.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival

Patton

Zubair

Khan

et al. 2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

Pancreatic tumors are highly desmoplastic and poorly‐vascularized, and therefore must develop adaptive mechanisms to sustain their survival under hypoxic condition. Extracellular vesicles (EV) play vital roles in pancreatic tumor pathobiology by facilitating intercellular communication. Here we studied the effect of hypoxia on the release of EVs and examined their role in adaptive survival of pancreatic cancer (PC) cells. Hypoxia promoted the release of EV in PC cell lines, MiaPaCa and AsPC1, wherein former exhibited a far greater induction. Moreover, a time‐dependent, measurable and significant increase was recorded for small EV (SEV) in both the cell lines with only minimal induction observed for medium (MEV) and large EVs (LEV). Similarly, noticeable changes in size distribution of SEV were also recorded with a shift toward smaller average size under extreme hypoxia. Thrombospondin (apoptotic bodies marker) was exclusively detected on LEVs, while Arf6 (microvesicles marker) was mostly present on MEV with some expression in LEV as well. However, CD9 and CD63 (exosome markers) were expressed in both SEV and MEVs with a decreased expression recorded under hypoxia. Among all subfractions, SEV was the most bioactive in promoting the survival of hypoxic PC cells and hypoxia‐inducible factor‐1α stabilization was involved in heightened EV release under hypoxia and for their potency to promote hypoxic cell survival. Altogether, our findings provide a novel mechanism for the adaptive hypoxic survival of PC cells and should serve as the basis for future investigations on broader functional implications of EV.

show abstract

“…The levels of alternatively spliced mRNAs can be heterogeneous between cells in a population (Waks et al 2011), and alternatively spliced transcripts may in turn play a role in various cell death phenotypes (Gang et al 2015; Schwerk & Schulze-Osthoff 2005). For example, alternative splicing of the BCL2 family members BCL2L1 and MCL1 can result in the production of both pro- and anti-apoptotic protein products, modulating the susceptibility of individual cells to apoptosis (Schwerk & Schulze-Osthoff 2005).…”

Section: Molecular Processes Implicated In the Generation Of Cellularmentioning

confidence: 99%

The impact of non-genetic heterogeneity on cancer cell death

Inde

Dixon

2017

Critical Reviews in Biochemistry and Molecular Biology

View full text Add to dashboard Cite

The goal of chemotherapy is to induce homogeneous cell death within the population of targeted cancer cells. However, no two cells are exactly alike at the molecular level, and sensitivity to drug-induced cell death therefore varies within a population. Genetic alterations can contribute to this variability and lead to selection for drug resistant clones. However, there is a growing appreciation for the role of non-genetic variation in producing drug tolerant cellular states that exhibit reduced sensitivity to cell death for extended periods of time, from hours to weeks. These cellular states may result from individual variation in epigenetics, gene expression, metabolism and other processes that impact drug mechanism of action or the execution of cell death. Such population-level non-genetic heterogeneity may contribute to treatment failure and provide a cellular ‘substrate’ for the emergence of genetic alterations that confer frank drug resistance.

show abstract

PDK2-mediated alternative splicing switches Bnip3 from cell death to cell survival

Abstract: In hypoxia, the survival property of cancer cells mediated by the glycolytic enzyme PDK2 is obligatorily linked to alternative splicing and generation of a novel isoform of death gene Bnip3, which suppresses mitochondrial injury and promotes survival.

Cited by 32 publications

References 29 publications

Long noncoding RNA DUXAP8 contributes to the progression of hepatocellular carcinoma via regulating miR‐422a/PDK2 axis

Long noncoding RNA DUXAP8 contributes to the progression of hepatocellular carcinoma via regulating miR‐422a/PDK2 axis

Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival

The impact of non-genetic heterogeneity on cancer cell death

Contact Info

Product

Resources

About