Alexander D. Boiko

Cedars-Sinai Medical Center

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Olga V. Razorenova

University of California, Irvine

Irving L. Weissman

Stanford University

Andrei V. Gudkov

Kola Science Centre

Elizabeth Finger

Western University

Sophia B. Chernikova

Stanford University

Barbara Bedogni

University of Miami

Amato J. Giaccia

University of Oxford

Renata Colavitti

Stanford University

Edward L. LaGory

Amgen (United States)

Marianne Broome-Powell

Stanford University

Cooperative Institutions

Stanford University

University of California, Irvine

Stanford Medicine

Health Research Institute of the Balearic Islands

University of Illinois Chicago

Palo Alto University

Cleveland Clinic

Cedars-Sinai Medical Center

University of California, San Francisco

Institute for Stem Cell Biology and Regenerative Medicine

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Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence

Genes & Development (2002)

Xianghong Zou Dipankar Ray Aileen Aziyu Konstantin Christov Alexander D. Boiko

A large number of human cancers display alterations in the Ink4a/cyclin D/Cdk4 genetic pathway, suggesting that activation of Cdk4 plays an important role in oncogenesis. Here we report that Cdk4- null mouse embryonic fibroblasts are resistant to transformation in response to Ras activation with dominant-negative (DN) p53 expression or in the Ink4a/Arf -null background, judged by foci formation, anchorage-independent growth, and tumorigenesis in athymic mice. Cdk4 -null fibroblasts proliferate at normal rates during early passages. Whereas Cdk4 +/+ Ink4a/Arf −/− cells are immortal in culture, Cdk4 −/− Ink4a/Arf −/− cells undergo senescence during continuous culture, as do wild-type cells. Activated Ras also induces premature senescence in Cdk4 −/− Ink4a/Arf −/− cells and Cdk4 −/− cells with DNp53 expression. Thus, Cdk4 deficiency causes senescence in a unique Arf/p53-independent manner, which accounts for the loss of transformation potential. Cdk4 -null cells express high levels of p21 Cip1/Waf1 with increased protein stability. Suppression of p21 Cip1/Waf1 by small interfering RNA (siRNA), as well as expression of HPV-E7 oncoprotein, restores immortalization and Ras-mediated transformation in Cdk4 −/− Ink4a/Arf −/− cells and Cdk4 −/− cells with DNp53 expression. Therefore, Cdk4 is essential for immortalization, and suppression of Cdk4 could be a prospective strategy to recruit cells with inactive Arf/p53 pathway to senescence.

Senescence

Malignant Transformation

Retinoblastoma protein

Cyclin-dependent kinase 4

Neoplastic transformation

10.1101/gad.1033002

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Citations (145)

Abstract LB-357: HIF-dependent over-expression of CUB domain-containing protein 1 stimulates migration in clear cell renal cell carcinoma

Cancer Research (2011)

Olga V. Razorenova Elizabeth Finger Renata Colavitti Sophia B. Chernikova Alexander D. Boiko

Abstract Kidney cancer is the sixth leading cause of cancer death in the USA, and the primary tumor is frequently accompanied by metastasis to lungs, liver, brain and bones. Importantly a large number of kidney cancer cases are characterized by loss of von Hippel-Lindau (VHL) gene, which leads to stabilization of hypoxia-inducible factors (HIFs), which contribute to tumor progression and metastasis by multiple mechanisms. CUB-domain-containing protein 1 (CDCP1) was shown to be expressed on the cell surface of metastatic cell lines and to increase the number of nodules formed by lung adenocarcinoma cells and melanoma in lungs in tail vein injection experiments, enhance peritoneal dissemination of scirrhous adenocarcinoma, and to induce metastasis in the chicken embryo metastatic model. In the present study we investigated the role of CDCP1 protein in clear cell renal cell carcinoma (CC-RCC) and found it to be upregulated in this disease entity by a mechanism of VHL loss through HIFs. Interestingly, we found CDCP1 protein expressed not only on the membrane of kidney cancer cell lines, but also to be secreted into the media as a full length isoform. Importantly, in the knockdown experiments we found CDCP1 to promote CC-RCC cell migration in vitro, the process known to be the key during metastasis. Accordingly CDCP1 participates in the signal transduction pathway leading to PKCδ phosphorylation in CC-RCC, stimulating migration. The role of PKCδ in CDCP1-dependent migration was verified by the PKCδ knockdown experiments, which phenocopy the effect of CDCP1 knockdown; as well as migration rescue experiments, where the impairment of migration caused by CDCP1 downregulation was rescued by the overexpression of constitutively active mutant of PKCδ. Furthermore, we showed a correlation of CDCP1 cell surface expression in primary tumor with poor patient outcome. Finally, we found that suramin, a drug, which showed the clinical benefit for CC-RCC patients at premetastatic stages, causes the downregulation of CDCP1 at the protein level. Thus, the further investigation of the role of CDCP1 protein in kidney cancer metastasis is important to validate CDCP1 as a therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-357. doi:10.1158/1538-7445.AM2011-LB-357

10.1158/1538-7445.am2011-lb-357

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Calreticulin is a Critical Cell Survival Factor in Malignant Neoplasms

PLoS Biology (2019)

Arum Han Chen Li Tara Zahed M K Wong Ian F. Smith

Calreticulin (CRT) is a high-capacity Ca2+ protein whose expression is up-regulated during cellular transformation and is associated with disease progression in multiple types of malignancies. At the same time, CRT has been characterized as an important stress-response protein capable of inducing immunogenic cell death (ICD) when translocated to the cell surface. It remains unclear why CRT expression is preserved by malignant cells during the course of transformation despite its immunogenic properties. In this study, we identify a novel, critical function of CRT as a cell survival factor in multiple types of human solid-tissue malignancies. CRT knockdown activates p53, which mediates cell-death response independent of executioner caspase activity and accompanied full-length poly ADP ribose polymerase (PARP) cleavage. Mechanistically, we show that down-regulation of CRT results in mitochondrial Ca2+ overload and induction of mitochondria permeability transition pore (mPTP)-dependent cell death, which can be significantly rescued by the mPTP inhibitor, Cyclosporin A (CsA). The clinical importance of CRT expression was revealed in the analysis of the large cohort of cancer patients (N = 2,058) to demonstrate that high levels of CRT inversely correlates with patient survival. Our study identifies intracellular CRT as an important therapeutic target for tumors whose survival relies on its expression.

Immunogenic cell death

10.1371/journal.pbio.3000402

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Citations (30)

Altered expression of ubiquitous kinesin heavy chain results in resistance to etoposide and hypersensitivity to colchicine: mapping of the domain associated with drug response.

PubMed (1998)

S A Axenovich Alexander R. Kazarov Alexander D. Boiko G Armin Igor B. Roninson

The motor protein kinesin is a tetramer consisting of two heavy and two light chains. Expression of an antisense RNA fragment derived from the mouse ubiquitous kinesin heavy chain (uKHC) cDNA is associated with a unique type of multidrug resistance. We analyzed the effects of retroviral transduction of the human uKHC and its derivatives on drug sensitivity of the human fibrosarcoma cell line HT1080. Surprisingly, overexpression of full-length uKHC and its variants that were deficient in the NH2-terminal motor domain produced a phenotype similar to that of antisense RNA, characterized by resistance to etoposide and collateral sensitivity to colchicine. This altered drug response, therefore, appears to be a general consequence of kinesin deregulation. The genetic suppressor element approach was applied to map the determinants of drug response in the kinesin heavy chain. A sense-oriented genetic suppressor element conferring resistance to etoposide was isolated from a retroviral library of randomly fragmented uKHC cDNA. This element encodes the last 55 amino acids of uKHC, suggesting that the COOH-terminal tail domain of uKHC is involved in the cellular drug response.

Kinesin

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Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors

Molecular Cancer (2023)

Pere Llinàs‐Arias Miquel Ensenyat-Méndez Sandra Íñiguez-Muñoz Javier I. J. Orozco B.C. Valdez

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. Methods We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. Results We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 − 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 − 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01). Conclusion Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.

CTCF

MMP1

Triple-negative breast cancer

Gene signature

10.1186/s12943-023-01906-8

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Therapeutic implications of melanoma heterogeneity

Experimental Dermatology (2016)

Stephanie J. Hachey Alexander D. Boiko

Over the last decade, the treatment of metastatic melanoma has been revolutionized by the translation of molecular insights into therapeutic benefit for patients. These include advances in immunotherapeutic and small-molecule approaches aimed at destroying cells with immunogenic antigens or gene mutations. Despite these advances, the limited durability of clinical response and eventual disease progression underscores a need for better understanding of mechanisms underlying tumor development. Current targeted therapies are developed partly based on the rationale that tumors are primarily clonal with respect to mutant oncogene or cell surface antigen target. However, with the advancement of cell isolation and transplantation approaches coupled with deep sequencing and mutation detection techniques, it has become increasingly clear that tumors are polyclonal. As a result, sensitive malignant cells are eradicated by treatment while the remaining tumor cell populations are conferred varying degrees of resistance and survival advantages by harbouring or acquiring certain epigenetic and genetic abnormalities. Tumor heterogeneity thus represents a major obstacle to the successful application of current therapies. Gaining insights into the cellular and molecular aspects of tumor diversity will not only facilitate the development and selection of therapeutic targets but also promote the evolution of precision medicine. In this viewpoint, we will discuss the implications of tumor heterogeneity for the treatment of metastatic melanoma and propose approaches to accelerate the translation of scientific discovery into improved clinical outcomes.

10.1111/exd.13002

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Citations (31)

NRF-1 transcription factor regulates expression of an innate immunity checkpoint, CD47, during melanomagenesis

Frontiers in Immunology (2024)

Kuldeep Makwana Edwin J. Velazquez Diego M. Marzese Bethany Smith Neil A. Bhowmick

Transmembrane integrin-associated protein

CD47

Transcription

10.3389/fimmu.2024.1495032

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Profiling Melanoma Heterogeneity Using Microwell RNA Cytometry

Methods in molecular biology (2016)

Ivan K. Dimov Alexander D. Boiko

Mass cytometry

10.1007/7651_2016_351

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CD271 is a molecular switch with divergent roles in melanoma and melanocyte development

Scientific Reports (2019)

Fabian V. Filipp Chen Li Alexander D. Boiko

Dysregulation of signaling networks controlling self-renewal and migration of developmental cell lineages is closely linked to the proliferative and invasive properties of tumors. Identification of such signaling pathways and their critical regulators is vital for successful design of effective targeted therapies against neoplastic tissue growth. The neurotrophin receptor (CD271/NGFR/p75NTR) is a key regulator of the melanocytic cell lineage through its ability to mediate cell growth, survival, and differentiation. Using clinical melanoma samples, normal melanocytes and global gene expression profiling we have investigated the role of CD271 in rewiring signal transduction networks of melanoma cells during neoplastic transformation. Our analysis demonstrates that depending on the cell fate of tumor initiation vs normal development, elevated levels of CD271 can serve as a switch between proliferation/survival and differentiation/cell death. Two divergent arms of neurotrophin signaling hold the balance between positive regulators of tumor growth controlled by E2F, MYC, SREBP1 and AKT3 pathways on the one hand, and differentiation, senescence, and apoptosis controlled by TRAF6/IRAK-dependent activation of AP1 and TP53 mediated processes on the other hand. A molecular network map revealed in this study uncovers CD271 as a context-specific molecular switch between normal development and malignant transformation.

Melanocyte

Microphthalmia-associated transcription factor

10.1038/s41598-019-42773-y

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Citations (26)

HIF-dependent over-expression of CUB domain-containing protein 1 stimulates migration in clear cell renal cell carcinoma

Cancer Research (2011)

Olga V. Razorenova Elizabeth Finger Renata Colavitti Sophia B. Chernikova Alexander D. Boiko

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