Serum-Nutrient Starvation Induces Cell Death Mediated by Bax and Puma That Is Counteracted by p21 and Unmasked by Bcl-xL Inhibition

Abstract

The cyclin-dependent kinase inhibitor p21 (p21WAF1/Cip1) is a multifunctional protein known to promote cell cycle arrest and survival in response to p53-dependent and p53 independent stimuli. We herein investigated whether and how it might contribute to the survival of cancer cells that are in low-nutrient conditions during tumour growth, by culturing isogenic human colorectal cancer cell lines (HCT116) and breast cancer cell lines in a medium deprived in amino acids and serum. We show that such starvation enhances, independently from p53, the expression of p21 and that of the pro-apoptotic BH3-only protein Puma. Under these conditions, p21 prevents Puma and its downstream effector Bax from triggering the mitochondrial apoptotic pathway. This anti-apoptotic effect is exerted from the cytosol but it is unrelated to the ability of p21 to interfere with the effector caspase 3. The survival function of p21 is, however, overcome by RNA interference mediated Bcl-xL depletion, or by the pharmacological inhibitor ABT-737. Thus, an insufficient supply in nutrients may not have an overt effect on cancer cell viability due to p21 induction, but it primes these cells to die, and sensitizes them to the deleterious effects of Bcl-xL inhibitors regardless of their p53 status.

The Essential Role of p53-up-regulated Modulator of Apoptosis (Puma) and Its Regulation by FoxO3a Transcription Factor in β-Amyloid-induced Neuron Death

“…These results suggest that p53 is induced and is required for neuron death in response to A␤. It is known that both A␤ and p53 induce BAX (2, 44, 45), which acts as a downstream effector of PUMA in the cell death cascade (46,47). Therefore, we checked the level of Bax and found that it was elevated in response to A␤ (Fig.…”

Adenovirus-mediated combined anti-angiogenic and pro-apoptotic gene therapy enhances antitumor efficacy in hepatocellular carcinoma

“…Previous evidence has shown that nutrition deprivation causes cancer cell death (30). Braun et al demonstrated that serum-nutrient starvation induces cell death mediated by Bax and Puma (31). However, under the condition of nutrient/oxygen depletion, cancer cells are expected to be more sensitive towards an apoptotic inducer.…”

Dietary restriction: could it be considered as speed bump on tumor progression road?

“…Braun et al [40] observed that starvation induces the increase of p21 levels in MCF7 cell lines independently from p53 and this mitigates the efficacy of the Puma/Baxdependent apoptotic signal (also induced by starvation). In addition, the anti-apoptotic function exerted by p21 in starved cells occurs upstream of mitochondrial permeabilization at the level of the Puma interactions with Bcl-x.…”