br T br Wenyi Gua Surong Suna c Andrew
Wenyi Gua,1, Surong Suna,c, Andrew Kahnb, Dalton Dacusb, Sebastian O. Wendelb, Nigel McMillana, , Nicholas A. Wallaceb, a School of Medical Sciences, Griﬃth University, Gold Coast Campus, Australia
b Division of Biology, Kansas State University, Manhattan, KS, United States of America
c Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China
High risk human papillomavirus (HPV) infections are the causative agent in virtually every cervical cancer as well as a host of other anogenital and oropharyngeal malignancies. These viruses must activate DNA repair pathways to facilitate their replication, while avoiding the K 252a arrest and apoptosis that can accompany DNA damage. HPV oncoproteins facilitate each of these goals, but also reduce genome stability. Our data dissect the cytotoxic and cytoprotective characteristics of HPV oncogenes in cervical cancer cells. These data show that while the transformation of keratinocytes by HPV oncogene leaves these cells more sensitive to UV, the onco-genes also protect against UV-induced apoptosis. Cisplatin and UV resistant cervical cancer cell lines were generated and probed for their sensitivity to genotoxic agents. Cervical cancer cells can acquire resistance to one DNA crosslinking agent (UV or cisplatin) without gaining broad tolerance of crosslinked DNA. Further, cisplatin resistance may or may not result in sensitivity to PARP1 inhibition.
Cervical cancers are the third most common and second deadliest cancer in women worldwide. Over half a million new cases of cervical cancer are diagnosed annually killing nearly 300,000 people (Parkin and Bray, 2006). Access to healthcare is a major factor in the devel-opment of cervical cancer with as many as 80% of cases occurring in developing countries (Sherris et al., 2001; Siegel et al., 2012; Tota et al., 2011). In addition to diﬀerences in screening and care, environmental factors (smoking and UV exposure for instance) increase the risk of cervical cancer (Fonseca-Moutinho, 2011; Godar et al., 2014). Nearly every cervical cancer is the result of a human papillomavirus infection (zur Hausen, 2002). This very large family of double stranded circular DNA viruses is divided into 5 genera based on sequence diﬀerences in their L1 major capsid gene (Bernard et al., 2010). While members of both the genus alpha and beta of human papillomaviruses are asso-ciated with cancer (Godar et al., 2014; Howley and Pfister, 2015; Wendel and Wallace, 2017), members of the genus alpha human pa-pillomaviruses are further divided into high risk and low risk papillo-maviruses based on the relative ability to cause cancer. Among the high
risk alpha papillomaviruses, human papillomaviruses 16 and 18 cause 70% of cervical cancers (Winer et al., 2006). In this manuscript, we will refer to these two viruses as simply as HPV.
Much is known about the molecular basis of how HPV manipulates the host cell both to promote its life cycle and to cause malignant transformation. Although the E5 protein from these viruses has onco-genic potential, the two canonical HPV oncogenes are HPV E6 and HPV E7 (Roman and Munger, 2013; Wallace and Galloway, 2015). HPV E6 binds a cellular ubiquitin ligase (E6AP) and uses it to promote p53 degradation (Huibregtse et al., 1991; Scheﬀner et al., 1993, p. 53). HPV E6 also activates the catalytic subunit of telomerase (Klingelhutz et al., 1996). HPV E7 disengages cell cycle checkpoints by degrading RB and RB family proteins (Dyson et al., 1989; Roman and Munger, 2013; Zhang et al., 2006). The lack of evolutionary pressure to mutate or otherwise inactivate these tumor suppressors results in tumors that are dependent on continued HPV E6 and E7 expression (Chang et al., 2010).