Enhanced expression of anti‐apoptotic proteins in human papillomavirus–immortalized and cigarette smoke condensate–transformed human endocervical cells: Correlation with resistance to apoptosis induced by DNA damage

Abstract

Apoptosis plays an important role in various biological processes including embryogenesis, differentiation, homeostasis, and oncogenesis. We have developed a system composed of primary human endocervical cells (HEN), HEN immortalized by human papillomavirus (HPV) type 16, and their counterparts subsequently malignantly transformed by cigarette smoke condensate (CSC). To understand the role of apoptosis in the multistep oncogenesis of human cervical cells, we examined the expression of apoptosis-associated proteins in our in vitro model system. The results showed no significant difference in the levels of apoptosis-inducing proteins bak and bax among all the cell types examined. On the other hand, the levels of apoptosis-inhibiting proteins bcl-2, bcl-xL and BAG-1 increased progressively after immortalization and transformation. The p53 protein level decreased in the HPV16-immortalized HEN and increased in one of two lines of the CSC-transformed HEN. Further, the increased levels of apoptosis-inhibiting proteins in the HPV16-immortalized and the CSC-transformed HEN correlated with progressively increased resistance of these cells to apoptosis induced by staurosporine or cisplatin. This study provided the first evidence that overexpression of apoptosis-inhibiting proteins is important for both multistep oncogenesis and resistance of human endocervical cells to apoptosis induced by DNA-damaging reagents.

Deregulated Bag‐1 protein expression in human oral squamous cell carcinomas and lymph node metastases

“…Two of the oral carcinoma cell lines had significantly higher levels. Yang et al 29. reported increased Bag‐1 S levels in HPV‐immortalized human endocervical cells after transformation by cigarette smoke condensate.…”

Surrogate endpoint biomarkers and their modulation in cervical chemoprevention trials

“…166 Yang et al demonstrated a similar resistance to apoptosis when E6-immortalized and E7-immortalized cell lines were exposed to cigarette condensate carcinogens. 167 Although these markers are expressed differentially in normal and high-risk tissue, to our knowledge they have not yet been shown to appear at a welldefined stage of carcinogenesis. Experimental evidence from cell lines suggests there may an interesting relation between apoptosis and antiapoptotic markers and HPV.…”

“…E6‐immortalized and E7‐immortalized cell lines have demonstrated decreased apoptosis, indicating that these immortalized cell lines have acquired genetic alterations that decrease sensitivity to apoptosis 166. Yang et al demonstrated a similar resistance to apoptosis when E6‐immortalized and E7‐immortalized cell lines were exposed to cigarette condensate carcinogens 167…”

Untitled

“…26 . Increased levels of Bcl-xL in the HPV16-immortalized and the CSCtransformed HEN, correlated with progressively increased resistance of these cells to apoptosis induced by staurosporine or cisplatin 27 . The ability of bcl-xL to prevent apoptotic cell death in response to chemotherapy-induced DNA damage and cell-cycle arrest may contribute to the accumulation of chromosomal aberrations within tumors.…”