Extensive body fat and muscle loss is a hallmark of cachexia which is associated with reduced response to therapy and duration of survival of patients suffering from chronic diseases such as cancer. Among various cancer types, pancreatic and gastric cancers are known to be associated with higher frequency of cachexia. Increased lipolysis in adipose tissue is implicated to be largely responsible for adipose mass loss and cancer cachexia. Adipose tissue-specific adipose triglyceride lipase (ATGL) catalyzing the initial rate-limiting step of lipolysis has been reported to play a key role in cachexia-associated adipose loss. Thus, inhibition of ATGL function would be an effective strategy to avoid cachexia during cancer therapies. Our long-term goal is to develop a therapeutic strategy to cancer cachexia using dietary small compounds. The objective of this application is to determine anti-cancer cachexia function of piceatannol, a resveratrol analogue. The central hypothesis is that piceatannol alleviates cancer-associated cachexia by targeting stability of ATGL and comparative gene identification-58 (CGI-58), an ATGL activator in adipose tissue. We recently identified that piceatannol exhibited an anti-adipogenic effect on adipocyte differentiation. In addition, our preliminary results further suggest that piceatannol, unlike resveratrol, inhibits pancreatic cancer cell-induced lipolysis in mature adipocytes possibly through proteolytic degradation of ATGL and CGI-58. Based on our strong preliminary data, our central hypothesis will be tested in two specific aims: 1) Examine the inhibitory effect of piceatannol on pancreatic cancer cell-induced lipolysis in adipocytes in vitro; and 2) Determine the physiological function of piceatannol in pancreatic cancer-induced cachexia in vivo.
In Aim 1, we will study the anti-lipolytic effect of piceatannol in adipocytes co-cultured with human pancreatic cancer cells.
In Aim 2, we will confirm the anti-lipolytic function of piceatannol in mouse model of pancreatic cancer cachexia. Furthermore, we will elucidate the molecular mechanism underlying piceatannol-inhibited pancreatic cancer cachexia-associated lipolysis. This finding will allow development of innovative strategy to treat cachexia-associated adipose tissue loss during cancer therapy.
Cancer cachexia is a key public health concern on the morbidity and mortality during cancer treatments. This proposed research is relevant to public health because the outcomes from this proposal will ultimately contribute to the development of a novel small molecule-based treatment of cancer cachexia-associated loss of fat mass, thereby improving efficacy of cancer therapies with improved survival and quality of life of patients.
