Abstract

Human papilloma virus (HPV) plays major roles in head and neck squamous cell carcinoma (HNSCC) pathogenesis. Paradoxically, HPV(+) HNSCC patients respond better to chemotherapy, such as cisplatin (CDDP), compared to HPV(-) HNSCC patients. However, molecular mechanisms and signaling pathways involved in HPV-mediated chemosensitivity are largely unknown. Thus, the overall goal of this application is to define the mechanisms involved in chemosensitivity of HNSCC cells in response to HPV infection with regard to ceramide metabolism and signaling. Our therapeutic goal is to utilize this mechanistic information for the development of novel strategies to enhance chemotherapy-induced HNSCC cell death and tumor suppression without HPV infection. Based on our novel and unpublished preliminary data, we propose a novel hypothesis that HPV16-E7 enhances CerS1/C18-ceramide-dependent lethal mitophagy in response to chemotherapy- induced cellular stress signaling, leading to enhanced HNSCC cell death and tumor suppression. This hypothesis will be tested in three Specific Aims: 1) Determine the roles of HPV16-E6 versus HPV16-E7 in the regulation of ceramide-mediated lethal mitophagy; 2) Determine the mechanisms by which HPV16-E7 signaling enhances ceramide-dependent lethal mitophagy; and 3) Define the therapeutic roles and mechanisms of HPV16-E7 signaling in the regulation of ceramide-dependent lethal mitophagy and HNSCC tumor suppression. Overall, these studies will help develop mechanism-based therapeutic strategies to induce HPV16-E7/C18-ceramide-mediated lethal mitophagy signaling for improving tumor suppression by chemotherapy in HNSCC patients.

Public Health Relevance

The overall goal of this application is to define the mechanisms involved in chemosensitivity of HNSCC cells in response to HPV infection with regard to ceramide metabolism and signaling, and to utilize this mechanistic information for the development of novel strategies to enhance chemotherapy-induced HNSCC cell death and tumor suppression without HPV infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016572-13
Application #
9514972
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wang, Chiayeng
Project Start
2005-04-01
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403

  Publications

Ramshesh, Venkat K; Lemasters, John J (2018) Imaging of Mitochondrial pH Using SNARF-1. Methods Mol Biol 1782:351-356
Ogretmen, Besim (2018) Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 18:33-50
Panneer Selvam, Shanmugam; Roth, Braden M; Nganga, Rose et al. (2018) Balance between senescence and apoptosis is regulated by telomere damage-induced association between p16 and caspase-3. J Biol Chem 293:9784-9800
Lv, Zongyang; Rickman, Kimberly A; Yuan, Lingmin et al. (2017) S. pombe Uba1-Ubc15 Structure Reveals a Novel Regulatory Mechanism of Ubiquitin E2 Activity. Mol Cell 65:699-714.e6
Thomas, Raquela J; Oleinik, Natalia; Panneer Selvam, Shanmugam et al. (2017) HPV/E7 induces chemotherapy-mediated tumor suppression by ceramide-dependent mitophagy. EMBO Mol Med 9:1030-1051
Gencer, Salih; Oleinik, Natalia; Kim, Jisun et al. (2017) TGF-? receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis. Sci Signal 10:
Lemasters, John J (2017) Evolution of Voltage-Dependent Anion Channel Function: From Molecular Sieve to Governator to Actuator of Ferroptosis. Front Oncol 7:303
Dany, Mohammed; Gencer, Salih; Nganga, Rose et al. (2016) Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML. Blood 128:1944-1958
Dany, Mohammed; Ogretmen, Besim (2015) Ceramide induced mitophagy and tumor suppression. Biochim Biophys Acta 1853:2834-45
Tirodkar, Tejas S; Lu, Ping; Bai, Aiping et al. (2015) Expression of Ceramide Synthase 6 Transcriptionally Activates Acid Ceramidase in a c-Jun N-terminal Kinase (JNK)-dependent Manner. J Biol Chem 290:13157-67

Showing the most recent 10 out of 39 publications