P53 apoptotic response to DNA damage dependent on bcl2 but not bax in head and neck squamous cell carcinoma lines

Abstract

In many tumors, the p53 gene has been mutated or deleted. p53 null mutant mice are prone to development of a variety of neoplasms at an early age. In head and neck cancer, p53 mutations are detected in most cases. p53 has been shown to induce growth arrest, differentiation, and death when overexpressed in cancer cell lines. p53 responds to DNA damage by arresting the cell cycle in G1 or G2 phase until repair can be completed. If DNA damage is severe, p53 may trigger programmed cell death by means of proapoptotic genes such as bax. Studies have suggested that p53 target genes must be intact for proper functioning of the tumor suppressor. We stably expressed transcriptionally active p53 in head and neck squamous cell carcinoma (SCC) lines in which the endogenous gene was inactivated by mutation. We performed proliferation, cell death, cell cycle, and gene expression analysis in control clones and those treated with the DNA damaging agent etoposide. These clones proliferated slowly with accumulation of cells at the G1/S phase boundary but did not undergo growth arrest or apoptosis. Coexpression of the proapoptotic gene bax (a known target of p53) failed to induce apoptosis in these clones. However, p53 expression sensitized these cells to DNA damage-induced apoptosis by means of inhibition of bcl2 protein levels. We concluded that the p53 apoptotic response to DNA damage was dependent on bcl2 but not bax in head and neck SCC lines.