Role of p16 and p14ARF in radio- and chemosensitivity of malignant gliomas

Abstract

In addition to cytoreductive surgery, most patients with malignant gliomas also undergo radio-and chemotherapy. An improved understanding of the molecular genetic mechanisms underlying the radio-and chemosensitivity of gliomas may help to identify glioma patients who will benefit from aggressive and, therefore, potentially toxic adjuvant treatment. It may also allow for the development of new therapies aimed at improving the response of these tumors towards chemo-and radiotherapy. The INK4a gene products, p16 and p14ARF, have been suggested as potential regulators of glioma chemo-and radiosensitivity. We have used tetracycline controlled expression of p16 and plasmid-based p14ARF expression to study the chemo-and radiosensitivity of glioma cell lines. Ectopic p16 sensitized U-87MG cells towards treatment with vincristine and possibly also BCNU by approximately 1.5 to 2-fold, and towards ionizing radiation by a factor of 1.5. p14ARF expression was found to render U-87MG cells 2-fold more radioresistant than controls. These findings support a role for p16 and p14ARF as modulators of the radio-and chemosensitivity of gliomas. Further studies of the role of cell cycle regulators in glioma chemo-and radio-sensitivity seem warranted. We would like to point out that such candidate genes which may code for potent growth suppressors (like p16) or even toxic gene products can be successfully investigated using the approach detailed in this manuscript.

Differential Roles of p16INK4A and p14ARF Genes in Prognosis of Oral Carcinoma

“…INK4A expression as radiosensitizer, whereas p14 ARF expression rendered radioresistance in glioma cell lines (25). Our observation also points to such an inference, supporting a role for p16 INK4A and p14 ARF as modulators of radioresponse in oral cancer.…”

“…A study by Ogi et al is the only available report that observed an association between p14 ARF methylation and better survival in carcinoma cases but they were unable to arrive at a conclusion for such a result (24). A recent report on glioma supports the role of p14 ARF as modulator for radioresistance (25). As radiation is the main mode of treatment in our patients, the absence of p14 ARF might be rendering the tumor cells more sensitive to radiation.…”

Aberrant methylation of p16 predicts candidates for 5-fluorouracil-based adjuvant therapy in gastric cancer patients

“…However, different studies of the relationship between the p16 gene and chemosensitivity have not always obtained the same results. [39][40][41][42][43] In a nasopharyngeal carcinoma (NPC) cell line, p16 transfection resulted in increased sensitivity to cisplatin and 5-FU, and p16 reduced NPC cell growth through G0/G1 arrest and modulation of the cellular response to chemotherapeutic drugs in NPC cells. 39 In a glioma cell line, p16 and p14ARF were modulators of radio-and chemosensitivity to vincristine and BCNU (carmustine).…”

Solute carrier protein family may involve in radiation-induced radioresistance of non-small cell lung cancer

“…For example, activation of c-raf-1 is positively correlated with radioresistance of head and neck squamous cell carcinomas (Dritschilo et al 2006), and p16 and p14ARF have also been suggested as potential regulators of glioma chemo-and radiosensitivity (Simon et al 2006). Radiotherapy is typically applied in a course of multiple fractions over several weeks (Ogawa et al 2006a).…”