Differential activation of NF-κB signaling is associated with platinum and taxane resistance in MyD88 deficient epithelial ovarian cancer cells

Gaikwad, Snehal; Thakur, Bhushan; Sakpal, Asmita; Singh, Ram Kumar; Ray, Pritha

doi:10.1016/j.biocel.2015.02.001

Cited by 31 publications

(32 citation statements)

References 40 publications

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“…Predominant presence of activated AKT contrasts this relatively dormant nature of late resistant cells, however, higher spheroid forming ability indicate greater degree of cellular quiescence and slower proliferation in these highly resistant population. This slow proliferative nature of the late resistant A2780 cells was reported earlier by us20. Recently, a rare subpopulation melanoma Rh123l ow stem like cells existing in quiescent and slow cycling stage showed to possess higher proportion of activated AKT compared to their Rh123 high counterpart cells35.…”

Section: Discussionsupporting

confidence: 73%

“…We have previously developed dynamic models of drug resistance against cisplatin, paclitaxel and both drugs by treating A2780 and OAW42 ovarian cancer cell lines with successive and gradually incrementing drug concentration and categorized them into early (ER) (Cis ER , Pac ER and Dual ER )and late (LR) (Cis LR , Pac LR and Dual LR ) resistant stages depending on their resistant indices20. Intriguingly, irrespective of the nature of drugs, elevated levels of IGF-1R and high phosphorylated AKT were found to be associated with early and late stages of resistance which seem to be essential for initiation (at early stage) and maintenance (late stage) of drug resistance19.…”

Section: Resultsmentioning

confidence: 99%

“…However, it is well known that response of ovarian cancer cells to platinum and taxol drugs are variable through differential gene signatures26. Earlier publication from our lab showed that induction of NF-kβ is essential for maintenance of only cisplatin resistance but not for paclitaxel resistance at late stages20. Thus, it is possible that a co-operative effect of IGF-1R along with other regulatory molecules exert differential levels of activation of the pluripotent genes during diverse drug resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Acquirement of resistance towards drug is a dynamic and multifactorial process and dominated by enrichment of CSC population. To understand this intricate relation between CSCs and enhanced drug resistance, we have used dynamic cellular models of resistance developed indigenously against Cisplatin, Paclitaxel and Dual drugs in A2780 and OAW42 ovarian cancer cells20. Based on the resistance indices, these cellular models are categorized into early and late resistant stages and shown to possess preferential up regulation of IGF-1R and activated AKT at early and late resistant stages respectively19.…”

Section: Discussionmentioning

confidence: 99%

“…Using indigenously developed resistant models against cisplatin, paclitaxel and dual drugs in ovarian cancer cells, we showed that upregulated IGF-1R expression is crucial to initiate resistance and an activated AKT later assists in maintenance of resistance1920. Irrespective of nature of drugs, early resistant (ER) cells of all these models show higher IGF-1R expression, while late resistant (LR) cells possess low IGF-1R but elevated phosphorylated AKT19.…”

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confidence: 99%

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An active IGF-1R-AKT signaling imparts functional heterogeneity in ovarian CSC population

Singh

Dhadve

Sakpal

et al. 2016

Sci Rep

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Deregulated IGF-1R-AKT signaling influences multiple nodes of cancer cell physiology and assists in migration, metastasis and acquirement of radio/chemoresistance. Enrichment of cancer stem cells (CSC) positively correlates with radio/chemoresistance development in various malignancies. It is unclear though, how IGF-1R-AKT signalling shapes CSC functionality especially in ovarian cancer. Previously we showed that upregulated IGF-1R expression is essential to initiate platinum-taxol resistance at early stage which declines with elevated levels of activated AKT at late resistant stage in ovarian cancer cells. Here, we investigated the effect of this oscillatory IGF-1R-AKT signalling upon CSC functionality during generation of chemoresistance. While gradual increase in CSC properties from early (ER) to late (LR) resistant stages was observed in three different (cisplatin/paclitaxel/cisplatin-paclitaxel) cellular models created in two ovarian cancer cell lines, the stemness gene expressions (oct4/sox2/nanog) reached a plateau at early resistant stages. Inhibition of IGF-1R only at ER and AKT inhibition only at LR stages significantly abrogated the CSC phenotype. Interestingly, real time bioluminescence imaging showed CSCs of ER stages possessed faster tumorigenic potential than CSCs belonging to LR stages. Together, our data suggest that IGF-1R-AKT signalling imparts functional heterogeneity in CSCs during acquirement of chemoresistance in ovarian carcinoma.

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Section: Discussionsupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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An active IGF-1R-AKT signaling imparts functional heterogeneity in ovarian CSC population

Singh

Dhadve

Sakpal

et al. 2016

Sci Rep

Self Cite

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KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer

Chen,

Johnson,

Jayamohan

et al. 2024

Molecular Carcinogenesis

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Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum‐based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy‐resistant disease. Recent studies have revealed that the epigenetic modifier lysine‐specific histone demethylase 1A (KDM1A/LSD1) is highly overexpressed in OCa. However, the role of KDM1A in chemoresistance and whether its inhibition enhances chemotherapy response in OCa remains uncertain. Analysis of TCGA datasets revealed that KDM1A expression is high in patients who poorly respond to chemotherapy. Western blot analysis show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A knockdown (KD) or treatment with KDM1A inhibitors NCD38 and SP2509 sensitized established and patient‐derived OCa cells to chemotherapy drugs in reducing cell viability and clonogenic survival and inducing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin‐resistant A2780‐CP70 cells to carboplatin treatment and paclitaxel‐resistant SKOV3‐TR cells to paclitaxel. RNA‐seq analysis revealed that a combination of KDM1A‐KD and cisplatin treatment resulted in the downregulation of genes related to epithelial‐mesenchymal transition (EMT). Interestingly, cisplatin treatment increased a subset of NF‐κB pathway genes, and KDM1A‐KD or KDM1A inhibition reversed this effect. Importantly, KDM1A‐KD, in combination with cisplatin, significantly reduced tumor growth compared to a single treatment in an orthotopic intrabursal OCa xenograft model. Collectively, these findings suggest that combination of KDM1A inhibitors with chemotherapy could be a promising therapeutic approach for the treatment of OCa.

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Dual Modality Imaging of Promoter Activity as a Surrogate for Gene Expression and Function

Dhadve

Thakur

Ray

2018

Methods in Molecular Biology

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Molecular functional imaging with optical reporter genes (both bioluminescence and fluorescence) is a rapidly evolving method that allows noninvasive, sensitive, real-time monitoring of many cellular events in live cells and whole organisms. These reporter genes with optical signatures when expressed from gene-specific promoters or Cis/Trans elements mimic the endogenous expression pattern without perturbing cellular physiology. With advanced recombinant molecular biology techniques, several strategies for optimal expression from constitutive or inducible, tissue-specific and weak promoters have been developed and used for dynamic and functional imaging. In this chapter, we provide an overview of the applications of this powerful technology for imaging gene expression in living cells and rodent models.

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Differential activation of NF-κB signaling is associated with platinum and taxane resistance in MyD88 deficient epithelial ovarian cancer cells

Cited by 31 publications

References 40 publications

An active IGF-1R-AKT signaling imparts functional heterogeneity in ovarian CSC population

An active IGF-1R-AKT signaling imparts functional heterogeneity in ovarian CSC population

KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer

Dual Modality Imaging of Promoter Activity as a Surrogate for Gene Expression and Function

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