Cervical cancer is the second most frequently diagnosed cancer and the second leading cause of cancer related deaths in women worldwide. American Indian (AI) women living on the Northern Plains have a greater incidence of cervical cancer and suffer from a higher mortality rate. Our recent studies have shown that AI women have more than twice the incidence of HPV infection and that HPV positive AI women have a two times higher likelihood of having abnormal PAP tests than HPV positive Caucasian women;suggesting underlying causes which increase HPV pathology. One potential cofactor may be smoke exposure and its effects on the host immune response and HPV oncogenesis. Our data indicate that 4 times more AI women smoke as compared to Caucasian women and the majority of HPV positive AI women smoke. While smoking is a recognized risk factor for cervical cancer, the molecular interactions between HPV and smoke compounds are unknown. Our laboratory has recently shown that smoke carcinogen Benzo[a]Pyrene (BaP) increases the expression of HPV oncoproteins, suggesting a direct molecular link between HPV infection and exposure to smoke. We have also identified that curcumin, a natural anti-cancer compound, effectively inhibits the expression of HPV oncoproteins. Based on this compelling evidence, we hypothesize that exposure to tobacco smoke synergizes with HPV infection and increases the incidence and severity of cervical cancer in American Indian women by increasing the expression of HPV oncoproteins (E6/E7) and modulating cellular/humoral immune responses. Additionally, we hypothesize that curcumin or nanocurcumin may be effective methods for the repression of HPV infection in AI women. We propose to 1) investigate novel mechanisms of synergy between HPV infection, BaP and the development of cervical cancer, 2) evaluate the efficacy of curcumin/nanocurcumin to suppress HPV oncogene expression in preclinical and clinical settings, and 3) to investigate the effect of smoke exposure on cervical immune responses. The results of this study will provide information regarding underlying etiological factors that are responsible for cervical cancer health disparity in AI women and will ultimately reduce the burden of cervical cancer.
Project Narrative American Indian (AI) women living in the Northern Plains have a greater incidence of cervical cancer and suffer from a higher mortality rate. This study will provide information regarding etiological factors that are responsible for cervical cancer health disparity in AI women, ultimately reducing the burden of cervical cancer in AI women and serving as a platform to reduce cervical cancer in other underserved populations.
|Gara, Rishi K; Kumari, Sonam; Ganju, Aditya et al. (2015) Slit/Robo pathway: a promising therapeutic target for cancer. Drug Discov Today 20:156-64|
|Sane, S; Abdullah, A; Boudreau, D A et al. (2014) Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells. Cell Death Dis 5:e1118|
|Ganju, Aditya; Yallapu, Murali M; Khan, Sheema et al. (2014) Nanoways to overcome docetaxel resistance in prostate cancer. Drug Resist Updat 17:13-23|
|Yallapu, Murali M; Khan, Sheema; Maher, Diane M et al. (2014) Anti-cancer activity of curcumin loaded nanoparticles in prostate cancer. Biomaterials 35:8635-48|
|Gara, Rishi Kumar; Sundram, Vasudha; Chauhan, Subhash C et al. (2013) Anti-cancer potential of a novel SERM ormeloxifene. Curr Med Chem 20:4177-84|
|Yallapu, Murali M; Ebeling, Mara C; Khan, Sheema et al. (2013) Novel curcumin-loaded magnetic nanoparticles for pancreatic cancer treatment. Mol Cancer Ther 12:1471-80|