The majority of cancers are diagnosed in people with advanced age. The development of cancer is highly associated with the aging process. The long-term goal of the lab is to elucidate the mechanism underlying the aging-related tumorigenesis. Autophagy is a membrane trafficking process leading to lysosomal degradation. Recently autophagy has been demonstrated by us and others as a novel tumor suppression mechanism. Interestingly, autophagy is also implicated in aging control. Morphological studies by electron microscopy indicated that autophagy is involved in the degradation of mitochondria, the organelles that play a critical role in both aging and tumorigenesis. This leads us to hypothesize that autophagy suppresses tumorigenesis through its function in mitochondria degradation. Compromised autophagy impairs the cell's ability to remove damaged mitochondria. Consequently, the intracellular ROS increase, which leads to genome instability and tumorigenesis. We and our collaborators have generated animal and cellular models that allow us test this hypothesis. Preliminary studies indicate that under stress the autophagy-compromised cells have increased ROS production and exhibit higher levels of one specific type of genome instability.
Three specific aims are proposed to further elucidate the mechanism by which autophagy suppresses tumorigenesis, in particular to, examine the contribution of mitochondrial alterations to the tumorigenesis caused by compromised autophagy: (1) to examine the impact of autophagy defect on mitochondria degradation and mitochondrial function;(2) to investigate in vivo the role of autophagy defect in causing genome instability, and to determine the contribution of the specific type of genome instability to the autophagy-related tumorigenesis;(3) to determine the contribution of mitochondrial dysfunction to the genome instability associated autophagy defect. This study would help better understand the development of a majority of age-related breast, ovarian, and prostate cancers. It will provide new insight into how aging and cancer development are inter-related. In addition, this study may provide a new paradigm for cancer prevention: reducing oxidative stress and preventing tumor by activating autophagy.
