PL 31. Autophage and urological cancers
Autophagy is one of the major pathways for degradation of cellular components in animal cells that controls the turnover of long-lived proteins and organelles. Although initially identified as a process induced by cellular starvation, an autophagic pathway is now recognized as the cellular response to a variety of stimuli including starvation, hormone treatment, virus infection and various stress conditions. It is unclear yet about the relationship between autophagy and malignancies, mostly it relies on the type of malignancy. Autophagy acts in both cancer progression and suppression. Recent studies show that the autophagy and apoptosis pathways are regulated by common factors, share common components and exert overlapping functions. For example, the blockage of autophagic signals increases apoptosis, whereas the inhibition of apoptosis may result in an autophagic programmed cell death.
Prostate cancer is very common in Western populations and is the second leading cause for male death from cancer in North America. In recent years, the morbidity of prostate cancer in China and other Asian countries has been also steadily rising. Androgen plays a critical role in the development and progression of prostate cancer. However, the regulatory role of androgen in the autophagic process and the function of the increased autophagosomes following androgen deprivation remain poorly understood. We found that autophagosomes, which were induced upon serum deprivation in LNCaP cells, can be significantly suppressed by dihydrotestosterone.
(DHT). Pharmacological inhibition of autophagy by 3-methyladenine led to increased apoptosis of LNCaP cells in serum-free medium compared to the medium with DHT or serum. Additionally, depletion of Beclin 1 to inhibit autophagy by small interfering RNA resulted in a slower proliferation of LNCaP cells in the medium depleted of serum than in the medium with DHT.
Altogether, these findings suggested that LNCaP cells can resort to the autophagic pathway to survive under androgen deprivation conditions, which can be a novel mechanism involved in the transition of prostate cancer cells from an androgen-dependent to an androgen-independent cell type.
Bladder cancer is the most common urinary cancer in China. Cisplatin- based chemotherapy has shown the survival benefit for the patients, but cisplatin-resistance renders the effect of chemotherapy. The mechanism of chemo-resistance is still unknown. We have found that cisplatin could cause autophagy on bladder cancer cells (T24) while the apoptosis triggered. The regulation autophagy process directly monitored the apoptosis program and its signal pathway. The results implied the connection between autophagy and apoptosis during bladder cancer chemotherapy. These results prospected the manipulated the autophagy to reduce the chemo-resistance on cisplatin.
It is well known that the VHL gene plays a definite role in the tumor genesis of Renal Cell Carcinoma. The growth factor receptors targeted therapy came to the clinical and showed good efficacy in recent years. Our research group has found the autophagy change between the tumor tissue and adjacent normal tissue. The mTOR signal pathway may play a dominant function on autophagy process. Our oncoming research will focus on EGF and VEGF signal pathway on autophagy and its internal relationship with mTOR and autophagy.
