The high-risk subtype Human Papillomaviruses (hrHPVs), including HPV16, HPV18, HPV31, HPV33, and HPV45, infect and oncogenically transform epithelial cells and cause squamous cell carcinomas and adenocarcinomas associated with the development of cervical cancer and subsets of vulvar, vaginal, penile, and anogenital cancers, as well as head-and-neck oropharyngeal carcinomas which often have poor clinical prognoses. Many cancers have been shown to contain elevated levels of the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR)-a glycolytic enzyme and antioxidant effector which frequently correlates with an aggressive tumor phenotype and serves as a determinant of therapy-resistance. We therefore tested whether siRNA-inhibition of TIGAR protein expression could sensitize HPV18-transformed HeLa cells to genotoxic chemotherapy agents (i.e., cisplatin, etoposide, doxorubicin, and 4-hydroxycyclophosphamide) that induce oxidative stress and DNA-damage. Here we demonstrate that the siRNA-knockdown of TIGAR hypersensitized HeLa cells to low, otherwise sub-inhibitory concentrations of these drugs and markedly induced cellular apoptosis, as compared to a scrambled RNA (scrRNA) oligonucleotide negative control or a non-transformed immortalized human fibroblast cell-line, HFL1. Importantly, these findings suggest that therapeutically inhibiting TIGAR could hypersensitize hrHPV+ cervical tumor cells to low-dosage concentrations of chemotherapy drugs that induce oxidative DNA-damage, which could potentially lead to more favorable clinical outcomes by reducing the adverse side-effects of these anticancer medications and making them more tolerable for patients. Our studies have further shown that siRNA-inhibition of TIGAR sensitizes HPV18+ HeLa cells to apoptosis induced by 4-hydroxycyclophosphamide-a DNA-alkylating agent these cells were reported to have resistance to, alluding to another possible benefit of targeting TIGAR in combinatorial treatment strategies against virus-induced cancers.
Published Date: 2021-05-31; Received Date: 2021-05-10