Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway plays a key role in the tumorigenesis of a variety of human cancers including ovarian cancer. However, inhibitors of this pathway such as Rad001 have not shown therapeutic efficacy as a single agent for this cancer. Arsenic trioxide (ATO) induces an autophagic pathway in ovarian carcinoma cells. We found that ATO can synergize with Rad001 to induce cytotoxicity of ovarian cancer cells. Moreover, we identified synergistic induction of autophagy and apoptosis as the likely underlying mechanism that is responsible for the enhanced cytotoxicity. The enhanced cytotoxicity is accompanied by decreased p-AKT levels as well as upregulation of ATG5–ATG12 conjugate and LC3-2, hallmarks of autophagy. Rad001 and ATO can also synergistically inhibit tumors in a xenograft animal model of ovarian cancer. These results thus identify and validate a novel mechanism to enhance and expand the existing targeted therapeutic agent to treat human ovarian cancer.
Nan Liu, Sheng Tai, Boxiao Ding, Ryan K Thor, Sunita Bhuta, Yin Sun and Jiaoti Huang
Lingfan Xu, Enze Ma, Tao Zeng, Ruya Zhao, Yulei Tao, Xufeng Chen, Jeff Groth, Chaozhao Liang, Hailiang Hu and Jiaoti Huang
ATM is a well-known master regulator of double strand break (DSB) DNA repair and the defective DNA repair has been therapeutically exploited to develop PARP inhibitors based on the synthetic lethality strategy. ATM mutation is found with increased prevalence in advanced metastatic castration-resistant prostate cancer (mCRPC). However, the molecular mechanisms underlying ATM mutation-driving disease progression are still largely unknown. Here, we report that ATM mutation contributes to the CRPC progression through a metabolic rather than DNA repair mechanism. We showed that ATM deficiency generated by CRISPR/Cas9 editing promoted CRPC cell proliferation and xenograft tumor growth. ATM deficiency altered cellular metabolism and enhanced Warburg effect in CRPC cells. We demonstrated that ATM deficiency shunted the glucose flux to aerobic glycolysis by upregulating LDHA expression, which generated more lactate and produced less mitochondrial ROS to promote CRPC cell growth. Inhibition of LDHA by siRNA or inhibitor FX11 generated less lactate and accumulated more ROS in ATM-deficient CRPC cells and therefore potentiated the cell death of ATM-deficient CRPC cells. These findings suggest a new therapeutic strategy for ATM-mutant CRPC patients by targeting LDHA-mediated glycolysis metabolism, which might be effective for the PARP inhibitor resistant mCRPC tumors.
Hongbing Chen, Yin Sun, Chengyu Wu, Clara E Magyar, Xinmin Li, Liang Cheng, Jorge L Yao, Steven Shen, Adeboye O Osunkoya, Chaozhao Liang and Jiaoti Huang
Small cell neuroendocrine carcinoma (SCNC) of the prostate is a variant form of prostate cancer that occurs de novo or as a recurrent tumor in patients who received hormonal therapy for prostatic adenocarcinoma. It is composed of pure neuroendocrine (NE) tumor cells, but unlike the scattered NE cells in benign prostate and adenocarcinoma that are quiescent, the NE cells in SCNC are highly proliferative and aggressive, causing death in months. In this study, we provide evidence that interleukin 8 (IL8)–CXCR2–P53 (TP53) signaling pathway keeps the NE cells of benign prostate and adenocarcinoma in a quiescent state normally. While P53 appears to be wild-type in the NE cells of benign prostate and adenocarcinoma, immunohistochemical studies show that the majority of the NE tumor cells in SCNC are positive for nuclear p53, suggesting that the p53 is mutated. This observation is confirmed by sequencing of genomic DNA showing p53 mutation in five of seven cases of SCNC. Our results support the hypothesis that p53 mutation leads to inactivation of the IL8–CXCR2–p53 signaling pathway, resulting in the loss of an important growth inhibitory mechanism and the hyper-proliferation of NE cells in SCNC. Therefore, we have identified potential cells of origin and a molecular target for prostatic SCNC that are very different from those of conventional adenocarcinoma, which explains SCNC's distinct biology and the clinical observation that it does not respond to hormonal therapy targeting androgen receptor signaling, which produces short-term therapeutic effects in nearly all patients with prostatic adenocarcinoma.