Abstract
Castration-resistant prostate cancer (CRPC) is a major clinical challenge for which no cure is currently available primarily because of the lack of proper understanding about appropriate molecular target(s). Previously we observed that inhibition of 5-lipoxygenase (5-Lox) activity induces apoptosis in some types of prostate cancer cells, suggesting an important role of 5-Lox in the viability of prostate cancer cells. However, nothing is known about the role of 5-Lox in the survival of castration-resistant, metastatic prostate cancer cells. Thus, we tested the effects of MK591, a second-generation, specific inhibitor of 5-Lox activity, on the viability and metastatic characteristics of CRPC cells. We observed that MK591 effectively kills the bone-invading C4-2B human prostate cancer cells (which bear characteristics of CRPC), but does not affect normal, non-cancer fibroblasts (which do not express 5-Lox) in the same experimental conditions. We also observed that MK591 dramatically inhibits the in vitro invasion and soft-agar colony formation of C4-2B cells. Interestingly, we found that treatment with MK591 dramatically down-regulates the expression of c-Myc and its targets at sub-lethal doses. In light of frequent over-activation of c-Myc in a spectrum of aggressive cancers (including CRPC), and the challenges associated with inhibition of c-Myc (because of its non-enzymatic nature), our novel findings of selective killing, and blockade of invasive and soft-agar colony-forming abilities of the castration-resistant, bone-metastatic C4-2B prostate cancer cells by MK591, open up a new avenue to attack CRPC cells for better management of advanced prostate cancer while sparing normal, non-cancer body cells.
Highlights
The American cancer society estimates that during the year 2014, about 233,000 new cases of prostate cancer will be diagnosed in the United States and about 29,480 will die from the disease which makes prostate cancer the most common form of malignancy and second-leading cause of cancer-related deaths in American men [1]
MK591 selectively decreases viability of the castration-refractory, bone-invading C4-2B prostate cancer cells. We found that both MK591 and 5-Lox shRNAs decrease the viability of LNCaP prostate cancer cells via induction of apoptosis [23]
Since most of the deaths due to prostate cancer happen due to androgen-resistant, metastatic disease, we wanted to examine whether MK591 can affect the bone-invading C4-2B prostate cancer cells which are androgen receptor positive but do not depend on androgenic-stimulus for their growth and survival
Summary
The American cancer society estimates that during the year 2014, about 233,000 new cases of prostate cancer will be diagnosed in the United States and about 29,480 will die from the disease which makes prostate cancer the most common form of malignancy and second-leading cause of cancer-related deaths in American men [1]. Current androgen deprivation therapy by decreasing circulating testosterone effectively shrinks androgen-dependent prostate tumors. Continuous androgen deprivation usually leads to recurrent castration-resistant prostate cancer which is a major clinical challenge in the management of prostate cancer [5,6]. CRPC patients who have failed hormone deprivation therapy are treated with standard docetaxelbased combination chemotherapy. Only limited improvement in survival was observed in these patients at the cost of a huge compromise with the quality of life [7], and there is no effective therapy for disseminated, late-stage prostate cancer. Lack of proper understanding about the biology of CRPC cells is hampering the development of effective therapies which are urgently needed in the clinic
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