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INTERCELLULAR COMMUNICATION AND ITS ROLE IN CANCER

Sinyuk, Maksim
http://rave.ohiolink.edu/etdc/view?acc_num=csu1542807565495878

Abstract Details

2018, Doctor of Philosophy in Regulatory Biology, Cleveland State University, College of Sciences and Health Professions.
To ensure proper coordination of normal tissue function, rapid intercellular communication is required between individual cells. Cells utilize adhesion complexes called gap junctions (GJs), specialized intercellular connections composed of connexin (Cx) proteins that allow direct transport of small molecules and ions between the cytoplasm of adjacent cells to communicate. GJ intercellular communication (GJIC) is an integral communication mechanism by which homeostasis is maintained to allow for precise cellular signaling as well as for the initiation and integration of signaling cascades and cellular function. However, connexin function in cancer biology remains poorly understood. To interrogate how connexins and GJIC contribute to tumorigenesis, I utilized cellular models of leukemia and ovarian cancer. These tumor types display common characteristics, including the need to engage in intercellular communication between individual cancer cells to drive proliferation and survival. To characterize communication between leukemia cancer cells, I employed preclinical in vitro models and measured GJ function through dye transfer assays. Clinically relevant GJ inhibitors, carbenoxolone (CBX) and 1-octanol, were utilized to uncouple the communicative capability of leukemia cells. A qRT-PCR screen identified Cx25 as a promising adjuvant therapeutic target in leukemia, and Cx25 but not Cx43 reduction via RNA interference decreased GJIC and sensitized cells to chemotherapy. In ovarian cancer, I sought to address how pharmacological inhibition of direct intercellular communication impacts tumor cell survival to serve as an additive novel therapeutic in both chemotherapy-sensitive and-resistant ovarian cancer. To validate that ovarian cancer cells are capable of coupling, I used transmission electron microscopy to directly visualize GJ-like structures between adjacent cells. I assessed dye transfer via surrogate cell-cell transfer assays and confirmed that ovarian cancer cells were capable of coupling and communication. To evaluate the consequence of blocking GJIC, I utilized a clinically relevant inhibitor with GJ disruption properties, mefloquine, and found that treatment reduced cisplatin- sensitive and-resistant ovarian cancer cell proliferation and increased apoptosis across all available models. These findings suggest that disruption of GJIC may be promising for both leukemia and ovarian cancer patients and demonstrate the means by which GJ-inhibiting strategies can be exploited for the development of novel anti-cancer therapies.
Justin Lathia, PhD (Advisor)
Ofer Reizes, PhD (Committee Member)
Alex Almasan, PhD (Committee Member)
Keith McCrae , MD (Committee Member)
Aaron Severson, PhD (Committee Member)
Angela Ting, PhD (Committee Member)
Zihua Gong, MD, PhD (Committee Member)
152 p.
Biology
Intercellular communication, cancer, connexin, gap junction

Recommended Citations

Citations

  • Sinyuk, M. (2018). INTERCELLULAR COMMUNICATION AND ITS ROLE IN CANCER [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1542807565495878

    APA Style (7th edition)

  • Sinyuk, Maksim. INTERCELLULAR COMMUNICATION AND ITS ROLE IN CANCER. 2018. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1542807565495878.

    MLA Style (8th edition)

  • Sinyuk, Maksim. "INTERCELLULAR COMMUNICATION AND ITS ROLE IN CANCER." Doctoral dissertation, Cleveland State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=csu1542807565495878

    Chicago Manual of Style (17th edition)

csu1542807565495878
160
© 2018, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.