Par-4 downregulation confers cisplatin resistance in pancreatic cancer cells via PI3K/Akt pathway-dependent EMT

Tan, Jiaxin; You, Yu; Xu, Tubin; Peng, Yu; Wu, Dingguo; Deng, Hao; Zhang, Yujun; Bie, Ping

doi:10.1016/j.toxlet.2013.10.008

Cited by 39 publications

(26 citation statements)

References 32 publications

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“…In NSCLC, the leading death cause is chemotherapy resistance and metastasis, yet the underlying mechanisms of them remain largely unclear [3]–[5]. Transforming growth factor-β1 (TGF-β1) can combine with the TGF-beta receptor 2 (TGFβR2) to activate the TGFβ signal pathway which has been suggested to be an important regulator of proliferation, apoptosis, epithelial-to-mesenchymal transition (EMT) and metastasis in various cancers [6]–[8].…”

Section: Introductionmentioning

confidence: 99%

miRNA 17 Family Regulates Cisplatin-Resistant and Metastasis by Targeting TGFbetaR2 in NSCLC

Jiang

Yin

et al. 2014

PLoS ONE

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MicroRNAs (miRNAs) have been proven to play crucial roles in cancer, including tumor chemotherapy resistance and metastasis of non-small-cell lung cancer (NSCLC). TGFβ signal pathway abnormality is widely found in cancer and correlates with tumor proliferation, apoptosis and metastasis. Here, miR-17, 20a, 20b were detected down-regulated in A549/DDP cells (cisplatin resistance) compared with A549 cells (cisplatin sensitive). Over-expression of miR-17, 20a, 20b can not only decrease cisplatin-resistant but also reduce migration by inhibiting epithelial-to-mesenchymal transition (EMT) in A549/DDP cells. These functions of miR-17, 20a, 20b may be caused at least in part via inhibition of TGFβ signal pathway, as miR-17, 20a, 20b are shown to directly target and repress TGF-beta receptor 2 (TGFβR2) which is an important component of TGFβ signal pathway. Consequently, our study suggests that miRNA 17 family (including miR-17, 20a, 20b) can act as TGFβR2 suppressor for reversing cisplatin-resistant and suppressing metastasis in NSCLC.

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Section: Introductionmentioning

confidence: 99%

miRNA 17 Family Regulates Cisplatin-Resistant and Metastasis by Targeting TGFbetaR2 in NSCLC

Jiang

Yin

et al. 2014

PLoS ONE

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“…The binding of PAR-4 with PKC inhibits the pro-survival activities of theses kinases (PKC zeta and lambda) and thus increasing PAR-4 pro-apoptotic activity [68]. Cisplatin is known for being able to downregulate PI3K downstream targets but resistance to this drug is also caused in part by a downregulation of Par-4 and an increase of the PI3K pathway [33, 71, 72]. Using PI3K inhibitors to increase Par-4, leading to an increase of cl-Par-4, in combination with a chemotherapeutic drug such as cisplatin is an interesting avenue to overcome cancer cells chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

“…These high levels of alteration in the PI3K/AKT/PTEN pathway indicate a potential issue for Par-4 activity, because of AKT1 negative regulation, in endometrial and ovarian cancers and are also known for being important key protein related to the chemoresistance of the feminine cancers [5, 6, 30–32]. Par-4 downregulation can also increase the components of the PI3K/AKT pathway, conferring resistance to chemotherapy to pancreatic cancer cells [33]. While previous publications have hinted at the crosstalk between the PI3K pathway and Par-4 dynamics, very little mechanistic work has been made toward the clarification of this relationship [24, 34].…”

Section: Introductionmentioning

confidence: 99%

Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells

et al. 2016

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We recently reported the caspase3-dependent cleavage of Par-4 resulting in the accumulation of a 25kDa cleaved-Par-4 (cl-Par-4) fragment and we investigated in the present study the mechanisms regulating this fragment using cl-Par-4-expressing stable clones derived from ovarian and endometrial cancer cell lines.Cl-Par-4 protein was weakly express in all stable clones despite constitutive expression. However, upon cisplatin treatment, cl-Par-4 levels increased up to 50-fold relative to baseline conditions. Treatment of stable clones with proteasome and translation inhibitors revealed that cisplatin exposure might in fact protect cl-Par-4 from proteasome-dependent degradation. PI3K and MAPK pathways were also implicated as evidenced by an increase of cl-Par-4 in the presence of PI3K inhibitors and a decrease using MAPK inhibitors. Finally using bioinformatics resources, we found diverse datasets showing similar results to those we observed with the proteasome and cl-Par-4 further supporting our data.These new findings add to the complex mechanisms regulating Par-4 expression and activity, and justify further studies addressing the biological significance of this phenomenon in gynaecological cancer cells.

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“…Par-4 is a very interesting protein because of its unique ability to induce apoptosis in a cancer-selective manner [170, 171]. Indeed, this unique mechanism of selectivity has been demonstrated in various models and also seemed to be involved in chemoresistance (including Tamoxifen, taxane and platinum agents) and tumorigenesis mechanisms [172–176]. As previously described, gynecological tissues are known for being hormone-dependent and, interestingly, it has been demonstrated that estrogen can downregulate Par-4 and thus could be involved in chemoresistance-associated mechanisms [177, 178].…”

Section: Chemoresistance In Gynecological Cancersmentioning

confidence: 99%

Chemoresistance and targeted therapies in ovarian and endometrial cancers

2016

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Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers.

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Par-4 downregulation confers cisplatin resistance in pancreatic cancer cells via PI3K/Akt pathway-dependent EMT

Cited by 39 publications

References 32 publications

miRNA 17 Family Regulates Cisplatin-Resistant and Metastasis by Targeting TGFbetaR2 in NSCLC

miRNA 17 Family Regulates Cisplatin-Resistant and Metastasis by Targeting TGFbetaR2 in NSCLC

Post-translational regulation of the cleaved fragment of Par-4 in ovarian and endometrial cancer cells

Chemoresistance and targeted therapies in ovarian and endometrial cancers

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