Therapeutic Targeting of Cancers with Loss of PTEN Function

Dillon, Lloye M.; Miller, Todd W.

doi:10.2174/1389450114666140106100909

Cited by 204 publications

(170 citation statements)

References 181 publications

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“…There have been limited effective solutions to solve the resistance problem in cancer treatment over the years 19, 21. Previous researches have demonstrated that PTEN is related with the drug resistance in various cancers 22. Our study gave evidence to the mechanistic connection of miR‐130b upregulation in cisplatin resistance in lung cancer.…”

Section: Discussionsupporting

confidence: 70%

MicroRNA‐130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β‐catenin pathway

Zhang

Sun

et al. 2018

Cell Biochemistry & Function

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More and more studies indicate the relevance of miRNAs in inducing certain drug resistance. Our study aimed to investigate whether microRNA‐130b‐3p (miR‐130b) mediates the chemoresistance as well as proliferation of lung cancer (LC) cells. MTS assay and apoptosis analysis were conducted to determine cell proliferation and apoptosis, respectively. Binding sites were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT‐PCR and immunoblot, respectively. Mouse xenograft model was used to evaluate the role of miR‐130b in cisplatin resistance in vivo. The rising level of miR‐130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. We identified PTEN as miR‐130b's major target and inversely correlated with miR‐130b expression in LC. Moreover, excessive miR‐130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. Suppression of miR‐130b enhanced drug cytotoxicity and reduced proliferation of A549/CR cells both internally and externally. Particularly, miR‐130b mediated Wnt/β‐catenin signalling pathway activities, chemoresistance and proliferation in LC cell, which was partially blocked following knockdown of PTEN. These findings suggest that miR‐130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/β‐catenin pathway. The rising level of miR‐130b in cisplatin resistance LC cell lines (A549/CR and H446/CR) versus its parental cell lines, indicated its crucial relevance for LC biology. Moreover, excessive miR‐130b expression promoted drug resistance and proliferation, decreased apoptosis of A549 cells. These findings suggest that miR‐130b targets PTEN to mediate chemoresistance, proliferation, and apoptosis via Wnt/β‐catenin pathway.

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Section: Discussionsupporting

confidence: 70%

MicroRNA‐130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β‐catenin pathway

Zhang

Sun

et al. 2018

Cell Biochemistry & Function

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“…The mechanistic link between the unique genomic features of SccRCC and response to checkpoint antibodies is being actively investigated. For PTEN -deficient tumors, several drugs are currently under clinical development in this setting including PI3K inhibitors, AKT inhibitors and PARP inhibitors (48). Circulating biomarkers for SccRCC have not yet been formally developed, but a recent study by Pal et al detected a high rate of TP53 mutations (64%) in the circulating tumor DNA of patients with clear-cell RCC treated with later lines of vascular endothelial growth factor inhibitors versus first-line treatment (31%) (49).…”

Section: Discussionmentioning

confidence: 99%

Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape

Wang

Kim

Peng

et al. 2017

Clinical Cancer Research

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Purpose Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity. Experimental Design We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of non-sarcomatoid RCC (RCC). We evaluated whole exome sequencing, single nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n=65) and RCC (n=598) across different parent RCC subtypes, including clear cell RCC, papillary RCC, and chromophobe RCC subtypes. Results SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFβ signaling across all subtypes. The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer related genes, despite a higher mutational burden in S-. Notably, sarcomatoid clear cell RCC (SccRCC) showed significantly fewer deletions at 3p21–25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared to clear cell RCC (ccRCC). A two-hit loss involving VHL predicted for ccRCC and a better prognosis whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis. Conclusions Sarcomatoid RCC segregates by parent subtype and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21–25 deletion and showing distinctive mutational and transcriptional profiles. These features prompt a more precise molecular classification of RCC with diagnostic, prognostic, and therapeutic implications.

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“…PTEN can be controlled by posttranslational regulation including phosphorylation, acetylation, methylation, oxidation, and so on (42, 43). Because PTEN may be regulated by ubiquitin-mediated proteasomal degradation, a common mechanism to control protein levels, insecurity of PTEN correlated with some of its mutations has been shown to comprise protein interactions (44). Casein kinase 2 mediated phosphorylation stabilizes PTEN protein in an inactive state by inhibiting its proteasomal degradation (45, 46).…”

Section: Characteristics Of Pten and Cancermentioning

confidence: 99%

Connection between Tumor Suppressor BRCA1 and PTEN in Damaged DNA Repair

et al. 2014

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Genomic instability finally induces cell death or apoptosis. The tumor suppressor, phosphatase and tensin homolog on chromosome 10 (PTEN), is a dual-specificity phosphatase, which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream PI3K/AKT targets. BRCA1, a well-known breast cancer tumor suppressor, is to associate with breast cancer risk and genetic susceptibility. Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses. The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors. Actually, the PTEN and BRCA1 genes are recognized as one of the most frequently deleted and/or mutated in many human cancers. The PI3K/AKT pathway is constitutively active in BRCA1-defective human cancer cells. Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments. This review summarizes recent findings of the function of BRCA1 and PTEN involved in genomic stability and cancer cell signaling.

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Therapeutic Targeting of Cancers with Loss of PTEN Function

Cited by 204 publications

References 181 publications

MicroRNA‐130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β‐catenin pathway

MicroRNA‐130b targets PTEN to induce resistance to cisplatin in lung cancer cells by activating Wnt/β‐catenin pathway

Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape

Connection between Tumor Suppressor BRCA1 and PTEN in Damaged DNA Repair

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