Cancer Stem Cell-Like Side Population Cells in Clear Cell Renal Cell Carcinoma Cell Line 769P

Huang, Bin; Huang, Yi; Yao, Zhaolin; Chen, Xu; Guo, Sheng; Mao, Xiao Peng; Wang, Dao Hu; Chen, Jun Xing; Qiu, Shaopeng

doi:10.1371/journal.pone.0068293

Cited by 40 publications

(41 citation statements)

References 35 publications

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“…The combination of Cis-P and ATO also depleted CSC, thereby offering yet other mechanisms for targeting RCC. The SP population in RCC may often be in G0/G1 although this may need more characterization (18,19). …”

Section: Discussionmentioning

confidence: 99%

“…Our studies included HuH-7 cells, which originated from an adult HCC (17), and displayed robust Cis-P-induced DDR (4). In these ways, we obtained information in respect to DDR in HK-2 cells, including cell growth regulation in the context of p53-related intracellular signaling, and the “side population (SP)” often associated with cancer stem cells (CSC) (18,19). This helped us to determine whether drugs could be identified with capacity for synergistically amplifying Cis-P toxicity in renal cells.…”

Section: Introductionmentioning

confidence: 99%

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Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma

et al. 2015

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Human papillomavirus (HPV) DNA integrations may affect therapeutic responses in cancers through ATM network-related DNA damage response (DDR). We studied whether cisplatin-induced DDR was altered in human HK-2 renal tubular cells immortalized by HPV16 E6/E7 genes. Cytotoxicity assays utilized thiazolyl blue dye and DDR was identified by gene expression differences, double-strand DNA breaks, ATM promoter activity, and analysis of cell cycling and side population cells. After cisplatin, HK-2 cells showed greater ATM promoter activity indicating activation of this network, but DDR was muted, since little γH2AX was expressed, DNA strand breaks were absent and cells continued cycling. When HK-2 cells were treated with the MDM2 antagonist inducing p53, nutlin-3, or p53 transcriptional activator, tenovin-1, cell growth decreased but cisplatin toxicity was unaffected. By contrast, arsenic trioxide, which by inhibiting wild-type p53-induced phosphatase-1 that serves responses downstream of p53, and by depolymerizing tubulin, synergistically enhanced cisplatin cytotoxicity including loss of SP cells. Our findings demonstrated that HPV16 E6/E7 altered DDR through p53-mediated cell growth controls, which may be overcome by targeting of WIP1 and other processes, and thus should be relevant for treating renal cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma

et al. 2015

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“…However cancer stem -like cells in five human RCC cell lines were identified [70]. These cells displayed high potential for proliferation and self-renewal, as well as strong resistance related to the ABCB1 transporter.…”

Section: Novel Dimensions In Comprehensive Approach the Mechanisms Ofmentioning

confidence: 99%

Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma

Kornakiewicz

Solarek²,

Bielecka³

et al. 2014

CST

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Mammalian target of rapamycin (mTOR) is a kinase protein involved in PI3K/AKT signaling with a central role in the processes of cell growth, survival and angiogenesis. Frequent mutations of this pathway make upstream and downstream components novel targets for tailored therapy design. Two mTOR inhibitors – everolimus and temsirolimus - enable an increase in overall survival (OS) or progression-free survival (PFS) time in a treatment of renal cancer. Despite recent advances in renal cancer treatment, resistance to targeted therapy is common. Understanding of molecular mechanisms is the basis of drug resistance which can facilitate prediction of success or failure in combinational or sequential targeted therapy. The article provides current knowledge on the mTOR signaling network and gives insight into the mechanisms of resistance to mTOR inhibitors from the complex perspective of RCC biology. The mechanisms of resistance developed not only by cancer cells, but also by interactions with tumor microenvironment are analyzed to emphasize the role of angiogenesis in ccRCC pathogenesis. As recent studies have shown the role of PI3K/AKT-mTOR pathway in proliferation and differentiation of cancer stem cells, we discuss cancer stem cell hypothesis and its possible contribution to ccRCC resistance. In the context of drug resistance, we also elaborate on a new approach considering ccRCC as a metabolic disease. In conclusion we speculate on future developments in agents targeting the mTOR pathway taking into consideration the singular biology of ccRCC.

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“…Previous studies have demonstrated that SPs within different cancer cells are less differentiated and have characteristics of stem/progenitor cells (7,16,21). In addition, it has been confirmed that SP cells in RCCs exhibit TIC characteristics (8,9,22). Fig.…”

Section: Fractionated Irradiated Cells Exhibit High Tumorigenicity Anmentioning

confidence: 63%

“…A number of studies have isolated pools of TICs from RCC cell lines and tumor specimens (9)(10)(11)(12)(13)(14). RCC TICs appear to be responsible for malignancy progression, relapse and metastasis (8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Tumor-initiating cells contribute to radiation resistance in primary human renal clear cell carcinomas by activating the DNA damage checkpoint response

Gao

et al. 2017

Oncology Letters

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Abstract. The use of radiotherapy in patients with clear cell renal carcinoma (ccRCC) is predominantly limited to palliation of metastases or control of local growth, because ccRCC cells readily develop radioresistance. The mechanisms underlying ccRCC resistance remain elusive. The present study demonstrated that ccRCC cells that survive fractionated radiation treatment display tumor-initiating cell (TIC) characteristics, such as high self-renewal and tumorigenic capacities, and overexpress stemness genes. ccRCC cells that survived fractionated radiation exhibited increased activation of the DNA damage checkpoint response and G2/M phase arrest compared with sham-irradiated cells. The results of the present study suggest that ionizing radiation destroys the bulk of tumor cells within ccRCC, but spares TICs; this subpopulation confers ccRCC radioresistance and may cause tumor recurrence or relapse following radiotherapy. Furthermore, these findings indicate that the DNA damage checkpoint response may serve as a potential therapeutic target for overcoming resistance of TICs in patients with ccRCC.

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Cancer Stem Cell-Like Side Population Cells in Clear Cell Renal Cell Carcinoma Cell Line 769P

Cited by 40 publications

References 35 publications

Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma

Arsenic trioxide amplifies cisplatin toxicity in human tubular cells transformed by HPV-16 E6/E7 for further therapeutic directions in renal cell carcinoma

Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma

Tumor-initiating cells contribute to radiation resistance in primary human renal clear cell carcinomas by activating the DNA damage checkpoint response

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