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Bergholz, Johann

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Bergholz

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Johann

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Bergholz, Johann
Author's Publications: search.filters.isAuthorOfPublication.be4a9373-ef6e-4617-a246-7c672f9f17cf

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    Metformin Sensitizes Leukemia Cells to Vincristine via Activation of AMP-activated Protein Kinase
    (Ivyspring International Publisher, 2017) Yi, Yong; Gao, Linfeng; Wu, Min; Ao, Juan; Zhang, Chunyan; Wang, Xiaodong; Lin, Min; Bergholz, Johann; Zhang, Yujun; Xiao, Zhi-Xiong Jim
    Vincristine is extensively used chemotherapeutic medicine to treat leukemia. However, it remains a critical clinical problem with regard to its toxicity and drug-resistance. AMP-activated protein kinase (AMPK) is an energy sensor that is pivotal in maintaining cell metabolic homeostasis. It is reported that AMPK is involved in vincristine-induced apoptosis. However, whether AMPK is involved in chemotherapy-resistance is largely unclear. It is well-documented that metformin, a widely used medicine to treat type II diabetes, possesses anti-cancer activities, yet whether metformin affects leukemia cell viability via vincristine is unknown. In this study, we showed that both AMPKα1 mRNA and phosphorylated AMPK protein levels were significantly decreased in clinical leukemia samples. We further demonstrated that metformin sensitized leukemia cells to vincristine-induced apoptosis in an AMPK-dependent manner. In addition, knockdown of AMPKα1 significantly reduced the effects of metformin on vincristine-induced apoptosis. Taken together, these results indicate that AMPK activation is critical in metformin effects on vincristine-induced apoptosis and suggest a putative strategy of a combination therapy using metformin and vincristine in treatment of leukemia.
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    PI3Kβ controls immune evasion in PTEN-deficient breast tumours
    (Springer Science and Business Media LLC, 2023-04-19) Bergholz, Johann; Wang, Qiwei; Wang, Qi; Ramseier, Michelle; Prakadan, Sanjay; Wang, Weihua; Fang, Rong; Kabraji, Sheheryar; Zhou, Qian; Gray, G. Kenneth; Abell-Hart, Kayley; Xie, Shaozhen; Guo, Xiaocan; Gu, Hao; Von, Thanh; Jiang, Tao; Tang, Shuang; Freeman, Gordon J.; Kim, Hye-Jung; Shalek, Alex K.; Roberts, Thomas M.; Zhao, Jean J.
    Loss of the PTEN tumor suppressor is one of the most common oncogenic drivers across all cancer types. PTEN is the major negative regulator of phosphoinositide-3 kinase (PI3K) signaling. Notably, the PI3Kβ isoform has been shown to play an important role in PTEN-deficient tumors, but the mechanisms underlying the importance of PI3Kβ activity remain elusive. Using a syngeneic genetically-engineered mouse (GEM) model of invasive breast cancer driven by concurrent ablation of Pten and Trp53 (p53), we showed that genetic inactivation of PI3Kβ led to a robust anti-tumor immune response that abrogated tumor growth in syngeneic immunocompetent mice, but not in immunodeficient mice. Mechanistically, PI3Kβ inactivation in the PTEN-null setting led to reduced STAT3 signaling and increased expression of immune stimulatory molecules, thereby promoting anti-tumor immune responses. Pharmacological PI3Kβ inhibition also elicited anti-tumor immunity, and synergized with immunotherapy to inhibit tumor growth. Mice with complete responses to the combined treatment displayed immune memory and rejected tumors upon re-challenge. Our findings demonstrate a molecular mechanism linking PTEN loss and STAT3 activation in cancer and suggest that PI3Kβ controls immune escape in PTEN-null tumors, providing a rationale for combining PI3Kβ inhibitors with immunotherapy for the treatment of PTEN-deficient breast cancer.