KLF9, a transcription factor induced in flutamide-caused cell apoptosis, inhibits AKT activation and suppresses tumor growth of prostate cancer cells

Shen, Pengliang; Sun, Jiabin; Xu, Guanghui; Zhang, Li; Yang, Zhaojuan; Xia, Shunren; Wang, Yang; Liu, Yongzhong; Shi, Guowei

doi:10.1002/pros.22812

Cited by 47 publications

(36 citation statements)

References 33 publications

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“…Genes with higher expression in MLL- vs. AT1-LNs whose gene products promote invasion and metastasis were for example, Gpr55 [88], Pla2g7 [78], and Mir130b [89]. Whereas genes associated with factors suppressing prostate tumor growth and metastasis like Klf9 , and Gpr68 [85, 90] were decreased in MLL- vs. AT1-LNs.…”

Section: Resultsmentioning

confidence: 99%

Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis

et al. 2017

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In order to grow and spread tumors need to interact with adjacent tissues. We therefore hypothesized that small but aggressive prostate cancers influence the rest of the prostate and regional lymph nodes differently than tumors that are more indolent. Poorly metastatic (Dunning AT1) or highly metastatic (Dunning MLL) rat prostate tumor cells were injected into the ventral prostate lobe of immunocompetent rats. After 10 days—when the tumors occupied about 30% of the prostate lobe and lymph node metastases were undetectable—the global gene expression in tumors, benign parts of the prostate, and regional iliac lymph nodes were examined to define tumor-induced changes related to preparation for future metastasis. The tumors induced profound effects on the gene expression profiles in the benign parts of the prostate and these were strikingly different in the two tumor models. Gene ontology enrichment analysis suggested that tumors with high metastatic capacity were more successful than less metastatic tumors in inducing tumor-promoting changes and suppressing anti-tumor immune responses in the entire prostate. Some of these differences such as altered angiogenesis, nerve density, accumulation of T-cells and macrophages were verified by immunohistochemistry. Gene expression alterations in the regional lymph nodes suggested decreased quantity and activation of immune cells in MLL-lymph nodes that were also verified by immunostaining. In summary, even when small highly metastatic prostate tumors can affect the entire tumor-bearing organ and pre-metastatic lymph nodes differently than less metastatic tumors. When the kinetics of these extratumoral influences (by us named TINT = tumor instructed normal tissue) are more precisely defined they could potentially be used as markers of disease aggressiveness and become therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis

et al. 2017

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“…Some KLF members are emerging as tumor-suppressor genes due to their roles in the inhibition of proliferation, migration, and induction of apoptosis (30,31). KLF2, as a member of KLF family, is diminished in many cancers and possesses tumor-suppressor features such as inhibition of cell proliferation mediated by KRAS (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression

Nie

Sun

Yang

et al. 2015

Molecular Cancer Therapeutics

336

291

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Recent evidence highlights long noncoding RNAs (lncRNA) as crucial regulators of cancer biology that contribute to essential cancer cell functions such as cell proliferation, apoptosis, and metastasis. In non-small cell lung cancer (NSCLC), several lncRNAs' expressions are misregulated and have been nominated as critical actors in NSCLC tumorigenesis. LncRNA ANRIL was first found to be required for the PRC2 recruitment to and silencing of p15 INK4B , the expression of which is induced by the ATM-E2F1 signaling pathway. Our previous study showed that ANRIL was significantly upregulated in gastric cancer, and it could promote cell proliferation and inhibit cell apoptosis by silencing of miR99a and miR449a transcription. However, its clinical significance and potential role in NSCLC is still not documented. In this study, we reported that ANRIL expression was increased in NSCLC tissues, and its expression level was significantly correlated with tumor-node-metastasis stages and tumor size. Moreover, patients with high levels of ANRIL expression had a relatively poor prognosis. In addition, taking advantage of loss-of-function experiments in NSCLC cells, we found that knockdown of ANRIL expression could impair cell proliferation and induce cell apoptosis both in vitro and vivo. Furthermore, we uncover that ANRIL could not repress p15 expression in PC9 cells, but through silencing of KLF2 and P21 transcription. Thus, we conclusively demonstrate that lncRNA ANRIL plays a key role in NSCLC development by associating its expression with survival in patients with NSCLC, providing novel insights on the function of lncRNA-driven tumorigenesis.

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“…42 Recently, KLF9 was reported to decreases resistance of prostate cancer cells to flutamide, an agonist of the androgen receptor 39 Cumulatively, these reports suggest that KLF9 is a promising anti-cancer target, however no known agents that can be utilized in cancer therapy specifically upregulate KLF9.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial thioredoxin reductase regulates major cytotoxicity pathways of proteasome inhibitors in multiple myeloma cells

et al. 2015

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It is generally accepted that intracellular oxidative stress induced by proteasome inhibitors is a byproduct of endoplasmic reticulum (ER) stress. Here, we report a mechanism underlying the ability of proteasome inhibitors bortezomib (BTZ) and carfilzomib (CFZ) to directly induce oxidative and ER stresses in multiple myeloma (MM) cells via transcriptional repression of a gene encoding mitochondrial thioredoxin reductase (TXNRD2). TXNRD2 is critical for maintenance of intracellular red-ox status and detoxification of reactive oxygen species. Depletion of TXNRD2 to the levels detected in BTZ- or CFZ-treated cells causes oxidative stress, ER stress and death similar to those induced by proteasome inhibitors. Reciprocally, restoration of near-wildtype TXNRD2 amounts in MM cells treated with proteasome inhibitors reduces oxidative stress, ER stress and cell death by ~46%, ~35% and ~50%, respectively, compared to cells with unrestored TXNRD2 levels. Moreover, cells from three MM cell lines selected for resistance to BTZ demonstrate elevated levels of TXNRD2, indirectly confirming its functional role in BTZ resistance. Accordingly, ectopic expression of TXNRD2 in MM cell xenografts in immunocompromised mice blunts therapeutic effects of BTZ. Our data identify TXNRD2 as a potentially clinically relevant target, inhibition of which is critical for proteasome inhibitor-dependent cytotoxicity, oxidative stress, and ER stress.

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KLF9, a transcription factor induced in flutamide-caused cell apoptosis, inhibits AKT activation and suppresses tumor growth of prostate cancer cells

Abstract: These data collectively showing that KLF9 substantially inhibits AKT activation and abrogates tumor growth of PCa cells, suggest the potential of either genetic or pharmacological activation of KLF9 in the therapeutic treatment of castration-resistant PCa.

Cited by 47 publications

References 33 publications

Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis

Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis

Long Noncoding RNA ANRIL Promotes Non–Small Cell Lung Cancer Cell Proliferation and Inhibits Apoptosis by Silencing KLF2 and P21 Expression

Mitochondrial thioredoxin reductase regulates major cytotoxicity pathways of proteasome inhibitors in multiple myeloma cells

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