Targeting Lactate Dehydrogenase-A Inhibits Tumorigenesis and Tumor Progression in Mouse Models of Lung Cancer and Impacts Tumor-Initiating Cells

Abstract

Summary The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the inter-conversion of pyruvate and lactate, is upregulated in human cancers and is associated with aggressive tumor outcomes. Here we use a novel inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by re-activation of mitochondrial function in vitro but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC including cancer stem cell-dependent drug resistant tumors.

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

“…To this end, multiple cancer biological models have been used in SIRM studies, including 2D and 3D cell culture, animal tumor models derived spontaneously from defined oncogenic lesions or from implanted tissue/cells, and human tumors analyzed in vivo or ex vivo following surgical resection (35). Regardless of the model, most tumors and derived cells profiled by SIRM recapitulate Warburg's original findings and disprove the canard that tumor cells necessarily have dysfunctional mitochondria (36) by demonstrating that Glc-derived 13 C incorporation into the Krebs cycle can be enhanced in cancerous versus paired non-cancerous tissues (37)(38)(39). Thus, SIRM profiling is excellently suited for uncovering novel aspects of cancer metabolism in model systems and directly in human subjects.…”

“…For example, recent studies have demonstrated the importance of the microenvironment for tumor metabolism either through immune modulation (22) or through direct regulation by stromal cells (93). Our group has demonstrated that ex vivo cultured tumor slices from primary tumors are viable metabolically and immunologically with the maintenance of the 3D tumor architecture and microenvironment (22,30,39,94). These ex vivo slices provide the unique opportunity to study the effects of environmental variants or drug treatment on metabolic networks directly in human tumors without systemic complications.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…These ex am ples il lus trate (I) the meta bolic speci fici ties of these tu mori genic sub pop u la tions ac cord ing to the can cer type, (II) the fact that in creased glu cose con sump tion and in creased ox ida tive me tab o lism are not nec es sary mu tu ally ex clu sive, and (III) the fact that glu cose con sump tion and lac tate pro duc tion are not nec es sar ily cou pled. In pan cre atic duc tal ade no car ci noma (PDAC), KRAS ab la tion re sis tant tu mor cells, which are re spon si ble of tu mor re lapses, were shown to de pend less on gly col y sis and more on OX PHOS to gether with dis play ing stem cell traits [238] [241]. No tably, a re sis tant sub pop u la tion of PDAC CSC clones showed in creased re sis tance to mi to chon dr ial tar get ing with met formin thanks to an in ter me di ate gly colytic/ res pi ra tory phe no type [241], high light ing the chal lenge of CSC meta bolic plas tic ity for tar get ing CSCs phar ma co log i cally.…”

“…For ex am ple, a sub set of pu ta tive ovar ian can cer stem cells (CD44 My D88 ) has been found to dis play a gly colytic meta bolic pro file over OX PHOS for their ATP gen er a tion [205], and a sub set of breast can cer cells able to grow as spheres in creas ingly rely on aer o bic gly col y sis and PPP flux com pared to the same cells grown in ad her ent con di tions [206]. Also, mod u la tion of spe cific gly colytic en zymes (i.e., de creased ex pres sion and ac tiv ity of pyru vate de hy dro ge nase or in creased ex pres sion or ac tiv ity of lac tate de hy dro ge nase A [LDHA]) plays a crit i cal role in pro mot ing the pro gly colytic phe no type of CICs in breast tu mors [237] and CSCs in lung tu mors [238].…”

Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors

“…More recently, there has been a resurgence of interest in targeting cancer metabolism (2-4) because it may not only be effective in inhibiting tumor growth, but may also provide a therapeutic window (5,6). For example, inactivation of lactate dehydrogenase-A (LDHA), an enzyme that catalyzes the final step of aerobic glycolysis, thereby reducing pyruvate to lactate, decreases tumorigenesis and induces regression of established tumors in mouse models of lung cancer driven by oncogenic KRAS or epidermal growth factor receptor (EGFR) while minimally affecting normal cell function (7). The finding that cancers have altered metabolism has prompted substantial investigation, both preclinically and in clinical trials, of several metabolically targeted agents, including those that elevate reactive oxygen species (ROS) or block glycolysis, lipid synthesis, mitochondrial function, and glutamine synthesis pathways (8).…”