Glutamine metabolism as potential target for prostate cancer

Radiotherapy is one of the most important treatments for many cancer types, including prostate cancer. Depending on the tumor stage, approximately 45% of patients with prostate cancer have a recurrence after radiation therapy. Many preclinical and clinical studies have shown that there are quite a number of the molecular mechanisms that contribute to tumor radiation resistance, including ability to repair DNA and activation of the signaling pathways driving tumor cell survival and proliferation. Tumor pathophysiological conditions such as inadequate oxygen supply and metabolic changes in tumor cells including the increased consumption of glucose are associated with a more aggressive tumor features and a high risk of recurrence after radiation therapy. One of the most important properties of cancer cells is global reprogramming of the energetic metabolism to support continuous tumor growth. Together with the increased glucose consumption, the cancer cells, which grow rapidly, need additional supplies for their biosynthesis. A significant proportion of the biosynthetic needs may be covered by the metabolism of amino acid glutamine as an important donor of nitrogen and carbon for the maintenance of tumor. Despite the fact that most normal tissues have the ability to synthesize glutamine, its external supply is of great importance for the fast-growing tumor tissues. Although many cancers require glutamine for survival and growth, tumors with enhanced expression of MYC oncogene including prostate cancer are particularly dependent on glutamine metabolism to sustain their growth. Recent studies showed that MYC oncogene is involved in prostate cancer initiation and progression by positive regulation of tumor cells called cancer stem cells (CSCs). CSCs are the only tumor cells capable to initiate tumor growth and relapse after therapy. A radiotherapy failure is attributed to the CSC population which was not completely removed during the treatment and caused tumor regrowth. Importantly, targeting of MYC inhibits the survival of prostate CSC and tumor formation. Our preliminary studies have additionally delivered proof that glutamine metabolism signaling with its key regulator MYC plays a critical role in the development of prostate cancer radioresistance by activation of the pro- survival mechanisms and DNA repair after radiotherapy. Our clinical study showed that MYC expression correlates with clinical outcome in patients with prostate cancer treated with radiotherapy. Accordingly, we will study the role of glutamine metabolism and associated signaling mechanisms for the development of prostate tumor radioresistance and tumor regrowth after radiotherapy by protecting CSCs from the radiation-induced free-radical production, by increasing DNA repair and by activating the tumor survival mechanisms. The results of this study can be used to develop the new biomarkers and the potential targets for individualized therapy.

Radiotherapy is one of the most important treatments for many cancer types, including prostate cancer. Depending on the tumor stage, approximately 45% of patients with prostate cancer have a recurrence after radiation therapy. Many preclinical and clinical studies have shown that there are quite a number of the molecular mechanisms that contribute to tumor radiation resistance, including ability to repair DNA and activation of the signaling pathways driving tumor cell survival and proliferation. Tumor pathophysiological conditions such as inadequate oxygen supply and metabolic changes in tumor cells including the increased consumption of glucose are associated with a more aggressive tumor features and a high risk of recurrence after radiation therapy. One of the most important properties of cancer cells is global reprogramming of the energetic metabolism to support continuous tumor growth. Together with the increased glucose consumption, the cancer cells, which grow rapidly, need additional supplies for their biosynthesis. A significant proportion of the biosynthetic needs may be covered by the metabolism of amino acid glutamine as an important donor of nitrogen and carbon for the maintenance of tumor. Despite the fact that most normal tissues have the ability to synthesize glutamine, its external supply is of great importance for the fast-growing tumor tissues. Although many cancers require glutamine for survival and growth, tumors with enhanced expression of MYC oncogene including prostate cancer are particularly dependent on glutamine metabolism to sustain their growth. Recent studies showed that MYC oncogene is involved in prostate cancer initiation and progression by positive regulation of tumor cells called cancer stem cells (CSCs). CSCs are the only tumor cells capable to initiate tumor growth and relapse after therapy. A radiotherapy failure is attributed to the CSC population which was not completely removed during the treatment and caused tumor regrowth. Importantly, targeting of MYC inhibits the survival of prostate CSC and tumor formation. Our preliminary studies have additionally delivered proof that glutamine metabolism signaling with its key regulator MYC plays a critical role in the development of prostate cancer radioresistance by activation of the pro-survival mechanisms and DNA repair after radiotherapy. Accordingly, we will study the role of glutamine metabolism and associated signaling mechanisms for the development of prostate tumor radioresistance and tumor regrowth after radiotherapy by protecting CSCs from the radiation-induced free-radical production, by increasing DNA repair and by activating the tumor survival mechanisms. The results of this study can be used to develop the new biomarkers and the potential targets for individualized therapy.