Perhaps you remember “The Lady Or The Tiger.” This classic tale tells of a princess long ago who secretly loved a commoner over her imperious father’s wishes. When the secret came out, the king brought the young man into the gladiators’ arena and placed him facing two doors. One opened to release a hungry tiger, which would rend the luckless suitor tooth and claw. Behind the other portal waited a beautiful young lady the jealous princess’s hated rival who would marry the commoner on the spot.
Just before choosing, the young man glanced up at the princess, who subtly signaled him the door to open. To which fate did she condemn her lover? (The author never let on.)
A similar Hobson’s choice, it now appears, might confront a cancer patient overdosed with drugs that activate the potent tumor suppressor, p53. At least that’s the scenario facing certain strains of mice in the laboratory of cancer biologist Lawrence Donehower at Baylor College of Medicine in Houston.
Donehower is senior author of a paper in the current issue of Nature, dated Jan. 3, 2002, titled: “p53 mutant mice that display early aging-associated phenotypes.”
“Basically this finding for the first time implicates p53 an important tumor suppressor gene in the aging process,” Donehower told BioWorld Today. “As it links tumor suppression to aging in general,” he added, “senescence might be one way of suppressing cancer.
“p53 may be important in both situations cancer and aging,” he continued. “One evolutionary theory about aging holds that as organisms lived longer, they had to evolve a critical protein like p53 to suppress tumors during their reproductive phases. But after the reproductive years it’s possible that there’s no further evolutionary fitness selection for this. So maybe some of the down side is that you already had tumor suppression early on, and you may get the effects on aging later in life.
“And maybe as part of its growth-inhibitory function,” Donehower suggested, “p53 could inhibit damaged cells from dividing, and thus prevent cancer. But later on in life it may inhibit cells generally, and block cell division when division may be necessary to provide cells for tissues to the aging body.”
Hyper-p53: Too Much Of A Good Thing
Donehower and his co-authors created mutant knockout mice carrying human cancers, in which the p53 protein is hyperactivated. As expected, the animals developed far fewer tumors than their normal littermates, but they didn’t live longer. “These mice had a life span shortened by about 23 percent,” he observed. “Their average life span was 96 weeks, compared with 118 weeks for normal mice. And they developed the stigmata of old age weight and muscle loss, hunched backs, brittle bones, osteoporosis, thin skin, reduced hair growth. Many organs showed reduced cellularity and atrophy, reduced responses to various stresses. Their experimental wounds took longer to heal. They didn’t tolerate anesthetic doses well.”
Donehower cited the part played in this research project by unanticipated consequences: “The unexpected side effect of this in vivo experiment,” he recounted, “was that we intended to make a p53-inactivating mutation but by accident we got an activating mutation instead, which was total serendipity.
“The hyperactive protein we obtained,” he went on, “is a truncated form. It contains only the C-terminal part of the p53 gene. Previous biochemical and cell culture studies have shown that C-terminal fragments and peptides in p53 are actually able to activate the protein, not inactivate it. So that’s what we think was going on: that this truncated p53 is activating the resident wild-type p53 in the cell, and causing it to become superactivated more activated as a tumor suppressor in response to the cell damage than normally. So we ended up finding a new role for the tumor-suppressor molecule.”
A “News & Views” commentary in Nature on Donehower’s paper, titled “The price of tumor suppression?” made a somewhat contrarian observation: “The [Baylor] results raise the disturbing possibility that the DNA-damaging drugs used to treat cancer in young people might prompt p53 into action and accelerate age-related disorders later on.”
Donehower’s reaction: “I think that may be exaggerated. The effects we’re seeing,” he added, “are the effects of p53 activity on the whole life span of the animal. My guess is a short-term transient application of a toxic drug or radiation probably won’t have a major effect on aging. Of course, long term is a different story. I think the worries about that are probably not as great as are out there. I would never say, Don’t take chemotherapy or radiation.’
“One of the things our results may do,” he predicted, “is speed the development, hopefully or give more reasons to develop more specific anticancer drugs, instead of these early broad-spectrum toxic agents that are being used now in cancer chemotherapy.”
Needed: More Specific Chemotherapy Drugs
Meanwhile, he said his laboratory is “following this up, looking for more markers of aging in these mice to convince ourselves that this is a true aging defect. The other thing we’re looking at are the stem cells in these mice, to see if they are deficient in proliferation. That’s what’s causing some of these atrophies we’re seeing. So we’re looking heavily at that area. And trying to generate other mouse models, which recapitulate this spectrum of p53 effects.”
The team presumes that the excess p53 stunts the stem cell division that normally replenishes tissues such as skin and bone in adults. “Our evidence suggests,” Donehower said, “that maybe certain aspects of aging may be related to adult tissue stem cells. This is an area that’s been overlooked. We propose that p53 may regulate stem cell proliferation, and that as a person ages that activity declines.”
Donehower made the point, “Our finding flies in the face of most aging research, which revolves around cellular damage and free oxygen radicals. Not a lot of people have thought about what happens in aging when there are not enough tissue stem cells to reconstitute various organs.”
The Baylor cancer researcher foresees no direct therapeutic utility from his group’s work. “This is a basic science story,” he observed. “I don’t think there are any clinical payoffs just something that’s conceptually interesting.” He concluded: “I don’t see any immediate benefits to the clinical biotech community.”