Abstract
Prostate cancer is the second most prevalent malignancy worldwide. In the early stages, the development of prostate cancer is dependent on androgens. Over time with androgen deprivation therapy, 20% of prostate cancers progress to a castration-resistant form. Novel treatments for prostate cancers are still urgently needed. Erianin is a plant-derived bibenzyl compound. We report herein that erianin exhibits anti-tumor effects in androgen-sensitive and castration-resistant prostate cancer cells through different mechanisms. Erianin induces endoplasmic reticulum stress-associated apoptosis in androgen-sensitive prostate cancer cells. It also triggers pro-survival autophagic responses, as inhibition of autophagy predisposes to apoptosis. In contrast, erianin fails to induce apoptosis in castration-resistant prostate cancer cells. Instead, it results in cell cycle arrest at the M phase. Mechanistically, C16 ceramide dictates differential responses of androgen-sensitive and castration-resistant prostate cancer cells to erianin. Erianin elevates C16 ceramide level in androgen-sensitive but not castration-resistant prostate cancer cells. Overexpression of ceramide synthase 5 that specifically produces C16 ceramide enables erianin to induce apoptosis in castration-resistant prostate cancer cells. Our study provides both experimental evidence and mechanistic data showing that erianin is a potential treatment option for prostate cancers.
Highlights
Prostate cancer (PCa) is the second most common cancer and the sixth highest cause of cancer-related mortality worldwide [1]
We examined whether erianin suppressed PCa cell migration by performing the wound healing assay (Figures 1C, D), following previous erianin studies in other cancer types [17, 19, 20]
We further identified that erianin exerted its antitumor activities via distinct mechanisms: a) In LNCaP cells, it activated multiple early and late unfolded protein responses (UPRs), indicative of Endoplasmic reticulum (ER) stress, which was associated with upregulation of pro-apoptotic Bcl-2 family members, Bim and Bax, and downregulation of antiapoptotic Bcl-2 and its sibling protein myeloid cell leukemia 1 (Mcl-1), leading to the execution of apoptosis as reflected by cleavage of caspase-3 and poly(ADPribose) polymerase (PARP)
Summary
Prostate cancer (PCa) is the second most common cancer and the sixth highest cause of cancer-related mortality worldwide [1]. 20% of patients receiving androgen deprivation therapy progress to castration-resistant PCa (CRPC) within 2-3 years. Androgen deprivation therapy has shown adverse effects, including cardiovascular, metabolic and cognitive morbidities [4]. Taxanes, such as docetaxel and cabazitaxel, are applied as primary chemotherapy in CRPC patients [3, 4, 6]. These chemicals can disrupt microtubule dynamics during both mitosis and interphase, leading to cell cycle arrest and even death in PCa [6, 7]. The prognosis and overall survival rate of PCa remain unsatisfactory, and searching for new treatment options is still the key matter in PCa research [6]
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