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

Brasseur, Kevin; Fabi, François; Adam, Pascal; Parent, Stefan; Lessard, Laurent; Asselin, Éric

doi:10.18632/oncotarget.9235

Cited by 12 publications

(9 citation statements)

References 73 publications

(95 reference statements)

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“…showed that cleaved Par-4 is also regulated by the proteasome. 40 We now report a stimulus-dependent regulation of Par-4 by the proteasome. That stimulus is cisplatin.…”

Section: Discussionmentioning

confidence: 72%

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells

Nguyen

Irby

2016

Cancer Biology & Therapy

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The prostate apoptosis response protein 4 (Par-4) is a tumor-suppressor that has been shown to induce cancer-cell selective apoptosis in a variety of cancers. The regulation of Par-4 expression and activity is a relatively understudied area, and identifying novel regulators of Par-4 may serve as novel therapeutic targets. To identify novel regulators of Par-4, a co-immunoprecipitation was performed in colon cancer cells, and co-precipitated proteins were identified by mass-spectometry. TRIM21 was identified as a novel interacting partner of Par-4, and further shown to interact with Par-4 endogenously and through its PRY-SPRY domain. Additional studies show that TRIM21 downregulates Par-4 levels in response to cisplatin, and that TRIM21 can increase the resistance of colon cancer cells to cisplatin. Furthermore, forced Par-4 expression can sensitize pancreatic cancer cells to cisplatin. Finally, we demonstrate that TRIM21 expression predicts survival in pancreatic cancer patients. Our work highlights a novel mechanism of Par-4 regulation, and identifies a novel prognostic marker and potential therapeutic target for pancreatic cancer.

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“…showed that cleaved Par-4 is also regulated by the proteasome. 40 We now report a stimulus-dependent regulation of Par-4 by the proteasome. That stimulus is cisplatin.…”

Section: Discussionmentioning

confidence: 72%

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells

Nguyen

Irby

2016

Cancer Biology & Therapy

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“…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 ]. A study demonstrated that Par-4 increase the apoptotic response to paclitaxel treatment in ovarian cancer cells [ 179 ].…”

Section: Chemoresistance In Gynecological Cancersmentioning

confidence: 99%

“…Our laboratory recently published a manuscript indicating that the cleaved form of Par-4 was highly reduced/absent in chemoresistant gynecological cancers indicating a potential venue for this protein to overcome this hurdle. This inhibition was post-translational and regulated by the PI3K and MAPK pathways, previously described as being involved in chemoresistance mechanisms [ 178 ]. Except these studies, the role of Par-4 on chemoresistance in gynecological cancer has received very little attention.…”

Section: Chemoresistance In Gynecological Cancersmentioning

confidence: 99%

Chemoresistance and targeted therapies in ovarian and endometrial cancers

2016

Self Cite

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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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“…Later, Treude et al demonstrated that caspase-8 also generates cl-Par-4 in response to TNFαand UV-induced apoptosis 67 . Indeed, cl-Par-4 was generated in response to a variety of anticancer agents effectively eliminating the cancer cells 33,34,[67][68][69][70] .…”

Section: Caspase-mediated Cleavage Of Par-4: the Cut That Always Bleedsmentioning

confidence: 99%

Prostate apoptosis response-4 and tumor suppression: it’s not just about apoptosis anymore

et al. 2021

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The tumor suppressor prostate apoptosis response-4 (Par-4) has recently turned ‘twenty-five’. Beyond its indisputable role as an apoptosis inducer, an increasing and sometimes bewildering, new roles for Par-4 are being reported. These roles include its ability to regulate autophagy, senescence, and metastasis. This growing range of responses to Par-4 is reflected by our increasing understanding of the various mechanisms through which Par-4 can function. In this review, we summarize the existing knowledge on Par-4 tumor suppressive mechanisms, and discuss how the interaction of Par-4 with different regulators influence cell fate. This review also highlights the new secretory pathway that has emerged and the likely discussion on its clinical implications.

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

Cited by 12 publications

References 73 publications

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells

TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells

Chemoresistance and targeted therapies in ovarian and endometrial cancers

Prostate apoptosis response-4 and tumor suppression: it’s not just about apoptosis anymore

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